IND and IDE Filing, Timelines, Paperwork

and Reports

February 24, 2012

Kate Marusina, PhD, MBA

CTSC Workshop

Agenda

UC Davis IND webpage– http://www.ucdmc.ucdavis.edu/clinicaltrials/IND/i

ndex.html

Definition and Responsibilities of Sponsor-investigator

When IND and IDE is required? How to file Timelines for approval Reports

Facilitate compliance with FDA, HHS and CMS regulations for clinical research

We provide:– Logistical support to clinical research

• IRB document preparation• Clinical Research Billing• FDA documentation (IND/IDE)• On-site help with study coordination• Metrics/data aggregation

– Education and Training– Monitoring and auditing of investigator-

initiated trials

Clinical Trials Support Group

Writing a grant?

CLINICAL RESEARCH SERVICES for grant budget purposes– IRB preparation (incl. annual reports): $500– Coverage Analysis (who pays for what): $500– FDA: IND or IDE submission: $5,000-$10,000– Monitoring (for investigator-initiated studies): $5000-

$10,000/year

Clinical Trials at UC Davis

NEW 2010 2011

exempt 247 317

expedited 284 316

full committee 141 228

facilitated 8 10

total 680 871

47%

3%

41%

6%

3%

Private Company

UC Davis Researcher

Coop Group

Researcher from other institution

Full Committee StudiesWho authored the protocol?

Other

Financial SponsorProvides funding for the studyMay or may not carry regulatory responsibilities Industry, Feds, Department, State, donors

Regulatory SponsorTrial design and oversightFiles the regulatory paperwork with the FDAIndustry, cooperative groups, investigator (sponsor-investigator)

InvestigatorConducts the studyAssurance of IRB approvalSafety and welfare of study subjectsConsentingRecord maintenance and reporting

Sponsor-Investigator

A Sponsor-Investigator is an individual who both initiates and conducts a clinical investigation and under whose immediate direction the investigational drug is being administered or dispensed.

Check your understanding

An investigator from Cancer Center wants to study an FDA approved drug in the new clinical trial. The investigator wrote the protocol, and a company provided the drug at no cost.

Who is the Regulatory Sponsor? Who is the Financial Sponsor?

Drug or Device?

intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals – Intended to affect the structure or any function of the

body

– intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of it's primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.

Check your understanding

Stem cells are extracted from patient’s peripheral blood and seeded onto plastic scaffold to recreate the organ

Is the new organ a drug or device?

Drug Development Plan

Pre

Clinical

Phase I Phase II Phase IVPhase III

NDA (New Drug Application)

RA775

IND (investigational New Drug Application) submission,30 day safetyreview

End of Phase IIMeeting

Pre-INDmeeting

Clinical planPre -clinical plan

What is IND?

Investigational New Drug application

21 CFR Part 312

Request for the FDA authorization to administer an investigational drug to humans

“ Any drug (or biologic) that is not generally recognized as safe and effective for use under the conditions prescribed, recommended or suggestedin the labeling thereof” Section 201 FD&C Act

Example of labeling

Do I need an IND?Drug is not yet approved by the FDA

Drug is approved by the FDA and marketed in the US

I use dietary supplement or botanical product

May be …

… if used for new indications,

new disease population or

different dose

different delivery

Yes May be …

… if used to cure, mitigate, diagnose or treat the disease

Dietary Supplements

Are INDs required for clinical studies of botanical products that are also lawfully marketed as dietary supplements in the U.S.?– Yes. If a lawfully marketed […]dietary supplement is

studied for its effects on diseases in the proposed investigation (i.e., to cure, treat, mitigate, prevent, or diagnose disease including its associated symptoms), then it is an investigational new drug and will be subject to IND requirements. This applies to studies in INDs sponsored for both commercial and academic research purposes.

Can be approved as a drug and still exist as a dietary supplement on the market

Structure-Function claims

Structure-function claims describe the effect a dietary supplement may have on the structure or function of the body– Promotes cardiovascular health– Provides antioxidant protection

Disease Claim

Disease claim - a claim to diagnose, cure, mitigate, treat, or prevent disease – Herceptin is indicated for the treatment of

patients with metastatic breast cancer whose tumors overexpress the HER2 protein…

– Require FDA approval– 10 criteria to decide whether it is a disease

claim Example: L-arginine for treatment of

severe asthma

Not sure? Ask the FDA!

Pre-IND request : Cover Letter + Information Package– Product Name– Chemical Name– Chemical Structure– Proposed Indication– Type of meeting requested (Type B)– Purpose of the meeting– Expected Meeting outcomes– Preliminary Agenda– List of proposed questions– Attendees– Requested FDA staff– Approximate date when the briefing package will be sent– Suggested dates and times for the meeting

Art of Writing Questions

What is it you are concerned about Propose the strategy and ask whether FDA

agrees with it FDA is not going give you solutions Example:

– Does the Agency agree that the proposed development plan and size of clinical safety database are appropriate ?

– Based on an analysis of the PK data, an initial dose of 0.20 mg/kg at an infusion rate of 5 nmol/L/min to attain a steady state serum concentration of 150 nmol/L was selected. Does the Agency concur with this approach?

Example of response

If IND is required

IND effective date

30 days

Annual Report Due

1 year date

Prepare and submit IND

Protocol AmendmentsInformation AmendmentsIND Safety Reports

IND Package

Cover Letter IND materials Form FDA 1571 Form FDA 1572 Form FDA 3674 (new app only)

Table of contents and examples on the website:– http://www.ucdmc.ucdavis.edu/clinicaltrials/IN

D/step4.html

Cover Letter

Address to:– Food and Drug Administration

Center for Drug Evaluation and ResearchCentral Document Room5901-B Ammendale Rd. Beltsville, MD 20705-1266Attn: Division Director

Has certain layout:– Drug, indication, phase of investigation– Any prior communication (i.e. pre-IND)– Contact information– Reaffirm that the clinical trial will not start until

IND goes into effect– Confidentiality statement

Form FDA 1571

Has to be current, always check– www.fda.gov, search for “IND”, IND Forms and

Instructions (left hand bar)– Form Approved OMB No 0910-0014

Expiration Date May 31, 2009 Required with EVERY communication regarding this IND (check different boxes)

Must be signed and dated Use Adobe Professional to save

changes

Form FDA 1572

Statement of Investigator– an binding agreement signed by the investigator– To assure that he/she will comply with FDA regulations

related to the conduct of a clinical investigation of an investigational drug or biologic.

– To assure that he/she is qualified to conduct the clinical investigation

Has to be current : www.fda.gov, search for “IND”, IND Forms and Instructions (left hand bar)

Form FDA 1572

Each new investigator has to sign –submit as Protocol Amendment

Is not required for the studies that are not done under IND

Form 3674

Attestation that the study information will be uploaded on clinicaltrials.gov

CTSC helps with upload– http://www.ucdmc.ucdavis.edu/clinicaltrials/Cli

nicalTrialsGov/clinicaltrialsgov.html

IND materials

Introductory Statement General Investigational Plan Investigator’s Brochure Protocol CMC Pharmacology and Toxicology Previous Human Experience Additional Information

Binders

3 copies of everything (cover page, 1571, info)

And Labels IND. NO. 106756

Safety and Efficacy of the Capsaicin Troche (0.1 mg) in treatment of individuals with dysphagia Serial 0006

Peter Belafsky, MD

University of California, Davis

What happens to IND after you send it?

Received at the Central Doc Rm Stamps IND with the receipt date IND # assigned Assigned to review division FDA will send you a Acknowledgement letter with

your IND # FDA has 30 days to respond If you do not hear within 30 days, can start the

study, but call first!

…or you get a Clinical Hold letter

Complete or Partial Typically, the FDA attempts to

resolve issues first

(out of > 15,000 CDER+CBER submissions per year)

Essential Requirements to Maintain IND

Stay current with IND amendments Submit Annual reports, even if you

did not enroll Submit Safety Reports Withdraw IND if needed

IND Amendments

Protocol Amendments [21 CFR 312.30]– New protocol /Change in the protocol (IRB approval

required after submission)

– New investigator (within 30 days of being added)

Information Amendments [21 CFR 312.33]– CMC

– Pharm/Tox

– Notice of discontinuance

IND Annual Reports

21 CFR 312.33

Even if did not enroll any patients

Can include various changes that were not captured in the Information and Protocol Amendments

Due within 60 days of the IND effective date (“anniversary date”)

See the website for examples and templates

IND Safety Reports 21 CFR 312.32 See website for submission requirements 15-day (calendar) report

– Notify FDA & all investigators in writing – Any serious and unexpected AE, associated w/ use of drug– any finding in laboratory animals that suggests a significant

risk for human subjects– Notify IRB

7-day (calendar) report – Notify FDA via phone or fax – Any fatal or life life-threatening AE associated w/ use of drug– Notify IRB

MedWatch Form 3500A

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

Mandatory reporting Make sure it is not Form 3500

(Voluntary reporting)

Withdrawing an IND

21 CFR 312.38 Sponsor may withdraw IND at any

time w/o prejudice– Notify FDA of the reasons– End clinical investigations– All drug stock disposed of or returned to the

drug manufacturer

Questions, comments?

Investigational Devices

Significant Risk (SR)– Intended to be used as an implant and – Purported to support or sustain human life– Is for a use of substantial importance in

diagnosing, curing, mitigating or treating disease

– Both FDA and IRB approvals required

Non-significant Risk (NSR)– Only IRB approval is required

Not Sure/ Ask the IRB or FDA

IRB makes SR/NSR determination Alternatively, FDA has pre-IDE

program– http://www.fda.gov/MedicalDevices/DeviceReg

ulationandGuidance/GuidanceDocuments/ucm126600.htm

Approved SR device for new indication most likely will require IDE

Exemptions

Example of FDA response

If IDE is required

ApprovalNot Approval

30 days

Prepare and submit IDE

Progress Reports (at least 1/year)SupplementsIDE Safety Reports

IDE Package

Cover Letter IDE materials Table of contents and examples on

the website:– http://www.ucdmc.ucdavis.edu/clinicaltrials/IN

D/IDE_Step4.html

Specifics of IDE applications

Design– Design controls

Manufacturing processes and device master records– Integrity testing– Sterilization (validation and testing)– Packaging– Electrical testing

Standards Risks (table)

IDE maintenance Safety reports

– Unanticipated Adverse Device Effect (within 10 days to the FDA)

– Also annual summary

Supplements– change in indication, – change in type or nature of study control, – change in primary endpoint, – change in method of statistical evaluation, and – early termination of the study (except for reasons

related to patient safety).

Progress reports

Questions, comments?

Clinical Trials Resource Group Kate

Marusina, Ph.D., MBA, Manager– IND/IDE submissions– EMR/Invision

Denise Owensby, Sr.CRC, CCRP

– Clinicaltrials.gov– Monitoring– IRB submissions

Virina de Jesus, Sr.CRC, CCRP– Monitoring– IRB submissions

Suzan Bruce, Coder for Research

– Coverage Analysis – Clinical Research Billing

Debie Schilling, Analyst– Data analysis

Clinical Trials Resource Group

Thank you!