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!
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