Regulatory Obligations for InvestigatorSponsored Research: An FDA Perspective

1
Regulatory Obligations for Investigator-Sponsored
ResearchAn FDA Perspective

• Nisha Jain, M.D
• Division of Hematology
• FDA Center for Biologics Evaluation and Research

2
Outline

• 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

3
FDA 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.

4
Legal 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.

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When 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

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When 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

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Sponsor Definition

• An individual, company, or institution who takes
  responsibility for and initiates a clinical
  investigation.
• Investigator-sponsored research may involve other
  sites.

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Sponsor-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.

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FDA 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.

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Responsibilities 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

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Responsibilities 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

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Sponsor/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!

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Sponsor/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

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Monitoring 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

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CBER 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

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FDA 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)

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Most 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

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Most 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

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Most 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

20
Most 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

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Contacts 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

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Related 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

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Links

• 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

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Links

• 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

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Acknowledgment

• Patricia Holobough
• Division of Inspections and Surveillance
• patricia.holobaugh_at_fda.hhs.gov
• 301-827-6347

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Back Up Slides

• The Inspection is Over What Happens
  Next?Possible FDA Enforcement Actions

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End 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

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• 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

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Actions 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

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Actions 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

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Actions for Inspected Party

• Refer to FDA Office of Criminal
• Investigations
• Injunction
• Seizure
• Prosecution
• Debarment if convicted of felony on
• FDA-related charges

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Actions 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

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Actions on Applications Terminate IND / Withdraw
IDE

• Ends all studies
• Sponsor recalls all unused drugs/devices
• Unless immediate hazard, requires Part 16 hearing

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Actions on Applications

• Withdraw Approval of NDA and PMA
• Revoke BLA

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Actions 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

36
FDAs 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