Title: Regulatory Obligations for InvestigatorSponsored Research: An FDA Perspective
1Regulatory Obligations for Investigator-Sponsored
ResearchAn FDA Perspective
- Nisha Jain, M.D
- Division of Hematology
- FDA Center for Biologics Evaluation and Research
2Outline
- FDA expectations for investigator-sponsored INDs
- Paradigms for submitting IND/IDEs to FDA
- Definition and responsibilities of
investigator-sponsored research - Types of violations found during inspections
3FDA Expectations for INDs
- FDA objective for reviewing an IND is to assure
the safety and rights of subjects in all phases
of the research, - In phase 2 and 3, to help assure that the quality
of the scientific evaluation is adequate to
permit evaluation of the drugs effectiveness and
safety 21 CFR 312.22(a) - The sponsor requirements to select qualified
investigators, ensure protocol compliance,
document, report, and monitor are based on these
objectives.
4Legal Framework for Requiring INDs and IDEs
- Laws require that FDA license certain products
before they can be sold in interstate commerce. - INDs and IDEs are permits that allow unapproved
drugs/devices to move in interstate commerce in
order to be studied.
5When Is an IND not required?
- The clinical investigation of a marketed drug
requires submission of an Investigational New
Drug (IND) application to FDA unless the clinical
investigation meets all of the following
conditions 21 CFR 312.2 (b) - The clinical investigation
- is not intended to be reported to FDA in support
of a new indication for use or to support any
other significant change in the labeling for the
drug - is not intended to support a change in the
advertising for the product - does not involve a route of administration or
dosage level, use in a subject population, or
other factor that significantly increases the
risks (or decreases the acceptability of the
risks) associated with the use of the drug
product
6When Is an IND not required?
- is conducted in compliance with the requirements
for IRB review and informed consent 21 CFR parts
56 and 50, respectively - is conducted in compliance with the requirements
concerning the promotion and sale of drugs 21
CFR 312.7 and - does not intend to invoke 21 CFR 50.24 Exception
from informed consent requirements for emergency
research
7Sponsor Definition
- An individual, company, or institution who takes
responsibility for and initiates a clinical
investigation. - Investigator-sponsored research may involve other
sites.
8Sponsor-Investigator
- An individual who both initiates and conducts an
investigation. - The term refers only to an individual. A
sponsor-investigator does not involve other
sites. - Must comply with the requirements of both an
investigator and a sponsor.
9FDA Expectations for Investigator-Sponsored
INDs/IDEs
- FDA regulations (21 CFR 312 or 812, 50, 54, and
56) apply to ALL sponsors and clinical
investigators. - EXCEPT sponsor-investigators do not need to
submit an investigator brochure to the IND. An
investigator brochure is required when other
sites are involved.
10Responsibilities of the sponsor /Investigator 21
CFR 312.50 312.59
- When a sponsor signs the form 1571, the sponsor
commits to the following - To wait 30 days from FDA receipt before beginning
the study - To not begin or continue the study if placed on
clinical hold - IRB(s) will be responsible for review and
approval of the study - To conduct the study in accordance with all
applicable regulatory requirements
11Responsibilities of IND Sponsor/Investigator
- Keep the IND current
- Select qualified sub investigators
- Provide all sub investigators with sufficient
information to conduct the investigation - Control the drug
- Prepare and maintain records
- Inform FDA of SAEs or newly identified risks to
subjects. - Monitor the ongoing investigations
12Sponsor/Investigator
- Must---
- Update the IND for new protocols, protocol
amendments, and new investigators21 CFR 312.30 - Update the IND with new information about the
product, toxicology, or discontinued
investigations 21 CFR 312.31 - Update the IND for Safety Reports 21 CFR 312.32
- Submit annual reports 21 CFR 312.33
- This is not a complete listing of
responsibilities!
13Sponsor/Investigator
- Must Monitor the Investigation to verify that
- The rights, safety, and welfare of human subjects
are protected - The reported clinical data are accurate, complete
(adequate and accurate) - The conduct of the trial is in compliance with
the protocol and regulations - Must correct problems or terminate a sites
participation, and report terminations
14Monitoring is NOT Optional
- Required by FDA regulation 21 CFR
- 312.50 Responsibilities of sponsors
- 312.53(d) Selecting monitors
- 812.25(e) Monitoring procedures
- Recommendations in guidance documents
- FDA Monitoring of Clinical Investigations
- http//www.fda.gov/ora/compliance_ref/bimo/clingu
id.html - ICH E6 Good Clinical Practice
- http//www.fda.gov/cder/guidance/959fnl.pdf
15CBER Investigator-sponsored INDs Active IND/IDEs
- IND/IDEs per sponsor/investigator
- 1 358
- 2 64
- 3 19
- 4-5 7
- 5-7 6
- 13 1
- Similar profile for CDER investigator-sponsored
INDs
16FDA Inspection of Investigator-Sponsored INDs
- Most of these inspections are DIRECTED
- complaints (subjects, staff, IRBs)
- requests from FDA reviewers
- FDA District-initiated (news reports)
- CBER Surveillance inspections of ongoing studies
(phases 1, 2, and 3)
17Most Common Clinical Investigator Violations
- Failed to follow protocol requirements
- Inadequate case histories
- Discrepancies between source records and CRF
- Inadequate drug/device accountability records
- Enrollment of ineligible subject
18Most Common Clinical Investigator Violations
- Failure to retain records
- Failed to notify the IRB of adverse events
- Lack of supporting raw data for CRF entries
- Failed to list all sub-investigators on Form FDA
1572 - Inadequate informed consent form
- Failed to report adverse events to the sponsor
19Most Significant Clinical Investigator Violations
- Enrolled ineligible subjects
- Enrollment exceeded protocol or IRB limit
- Did not conduct required evaluations
- (related to safety assessments)
- Violated clinical hold
- Submitted false information to the sponsor
- Use of drug/device before submission of IND/IDE
20Most Significant Clinical Investigator Violations
- Clinicians used unapproved product without IND
- Sponsor shipped product to sites not named in IND
(failure to maintain IND, lack of Form1572) - Failed to monitor progress of study / did not
obtain information from sites - Failed to report SAEs to IND
- Promoted the product
21Contacts to Find Out if the Research Needs an IND
or IDE
- Drugs
- CDER Division of Drug Information
- 301-827-4573 druginfo_at_cder.fda.gov
- Biologics
- CBER Manufacturers Assistance 800-835-4709
301-827-1800 matt_at_cber.fda.gov - Devices
- CDRH Manufacturers Assistance 800-638-2041
dsmica_at_cdrh.fda.gov
22Related links
- FDA Regulations 21 CFR 312 Investigational New
Drug Application - http//www.access.gpo.gov/nara/cfr/waisidx_04/21cf
r312_04.html - FDA Information Sheet Guidance Off Label and
Investigational Use of Marketed Drugs, Biologics,
and Medical Devices - http//www.fda.gov/oc/ohrt/irbs/offlabel.html
- FDA Information Sheet Guidance Emergency Use IND
- http//www.fda.gov/oc/ohrt/irbs/drugsbiologics.htm
lemergency
23Links
- FDA Information Sheet Guidance Treatment IND
- http//www.fda.gov/oc/ohrt/irbs/drugsbiologics.htm
ltreatment - FDA FAQs Frequently Asked Questions on Drug
Development and Investigational New - Drug Applications
- http//www.fda.gov/cder/about/smallbiz/faq.html
24Links
- Information on Submitting an Investigational New
Drug Application for a Biological Product - http//www.fda.gov/cber/ind/ind.htm
- FDA FAQs Center for Biologics Evaluation and
Research (CBER) Frequently Asked - Questions
- http//www.fda.gov/cber/faq.htm
25Acknowledgment
- Patricia Holobough
- Division of Inspections and Surveillance
- patricia.holobaugh_at_fda.hhs.gov
- 301-827-6347
26Back Up Slides
- The Inspection is Over What Happens
Next?Possible FDA Enforcement Actions
27End of the Inspection
- Form FDA-483 is presented and discussed
- You may respond in a letter - send to address on
the Form FDA-483. - You may also ask the FDA investigator for the HQ
Center address
28- The inspection report is written by the FDA
investigator and sent to the Center. - The Center evaluates the report and determines
the corrective action, and classifies the
inspection. - NAI, VAI or OAI
- We write a letter following most inspections
29Actions for Inspected Party Warning Letter
- One or more activities is in violation of laws or
regulations. - Failure to take action may result in
administrative or regulatory action without
further notice - 15 day response
- Posted on FDA web page
30Actions for Inspected Party Initiate CI
Disqualification
- Notice of Initiation of Disqualification
Proceeding and Opportunity to Explain (NIDPOE) - Posted on FDA web page
- Disqualified investigators may not receive
investigational products - No requirement to issue warning letter before
NIDPOE
31Actions for Inspected Party
- Refer to FDA Office of Criminal
- Investigations
- Injunction
- Seizure
- Prosecution
- Debarment if convicted of felony on
- FDA-related charges
32Actions on ApplicationsReject the Data
- FDA may determine that the data are unreliable
(inaccurate / incomplete) - The remaining data would need to be reanalyzed.
- Might require an additional study
- Might delay approval of a BLA/NDA/PMA
33Actions on Applications Terminate IND / Withdraw
IDE
- Ends all studies
- Sponsor recalls all unused drugs/devices
- Unless immediate hazard, requires Part 16 hearing
34Actions on Applications
- Withdraw Approval of NDA and PMA
- Revoke BLA
35Actions on ApplicationsApplication Integrity
Policy
- Agency will defer substantive review of
applications - Untrue statements of material facts pattern or
practice of wrongful acts - bribes
- Require corrective action plan
36FDAs Electronic Freedom of Information Reading
Room
- www.fda.gov/foi/electrr.html
- Warning letters
- Clinical Investigators
- NIDPOEs and NOOHs
- Disqualified and restricted CIs
- Presiding officer decisions
- Firms under Application Integrity Policy