1. Investigator-held IND Studies
Jeffrey W. Clark, MD
DF/HCC Medical Director for Clinical Trials Operations
April 25, 2008

2. Regulations allow an individual to be both study sponsor (IND holder) and clinical investigator

3. Objectives Describe factors that influence whether an IND is required
Explain the regulatory requirements for an IND
Identify strategies for fulfilling IND holder (sponsor-investigator) obligations 3 3

4. Role of the FDA
Federal agency responsible for ensuring safe and accurately represented products
Includes drugs, biologics, medical devices, and radiation-emitting products
Oversees clinical investigations of FDA-regulated products
Any funding source
Academic center or other U.S. location
Purpose of marketing or scientific knowledge

5. FDA Centers Center for Drug Evaluation and Research (CDER)
Divided into three centers relevant to clinical research
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiologic Health (CDRH)
FDA
CDER
CBER
CDRH 5 5

6. Center for Drug Evaluation and Research (CDER)
Responsible for regulating drugs, chemical entities and proteins
Allows shipment of investigational products for research upon submission of an Investigational New Drug application (IND)

7. Center for Biologics Evaluation and Research (CBER)
Responsible for regulating biological and related products
Blood, vaccines, tissues, cellular and gene therapies
Allows the study of biological products upon submission of an Investigational New Drug application (IND)

8. Center for Devices and Radiologic Health (CDRH)
Responsible for regulating medical devices and radiation-emitting products
Allows the clinical study of medical devices upon submission of an Investigational Device Exemption (IDE)

9. Unapproved Product(s) Approved Product(s)
When is an IND required?
Unapproved Product(s)
Approved Product(s)
Required for new drug or biologic use in a clinical trial
Usually required to study a new aspect of an approved product
Different indication
Different administration or dosage level
New drug combination
Different population
Source: 21 CFR 312.2 9 9

10. Off-label Use in the Practice of Medicine
Approved products may be used by physicians outside of labeled indications for the practice of medicine
No IND is needed
Source: 21 CFR 312.2

11. When is an IND not required?
Generally not required when all criteria met:
No intent to support new use or labeling change
No intent to support change in advertising
No factor such as route of administration, dosage, or study population significantly increases risk
Compliance with FDA informed consent and IRB review requirements
No promotion or representation of product as safe or effective treatment for condition under study
Source: 21 CFR 312.2

12. Best Practice
It’s a much safer path to file an IND application and have it deemed exempt than not to file and later be subject to a determination that an IND should have been requested 12 12

13. Never Forget the IRB
Whether an IND is or is not required, all clinical research must have IRB review and approval

14. Study Start-up Procedures
Discuss the study concept with the Disease Program
Draft the protocol
Use the biomedical protocol template and guidance documents created by DF/HCC

15. IND Submission Process
Sponsor-Investigator prepares and submits in triplicate to appropriate FDA Center:
FDA Form-1571
FDA Form-1572
FDA Form-3674
Helpful hint: A single IND may be utilized for one or more phases (I, II, or III) of an investigation, or for multiple protocols related to the IND purpose and indication.

16. Form FDA-1571
Contractual agreement between Sponsor-investigator and FDA to:
Wait 30 days post IND submission before beginning research
Unless earlier notification indicates research can begin
Not begin or continue the research if placed on clinical hold
Use an IRB for initial and ongoing review and approval of the research
Conduct research in accordance with all applicable regulatory requirements
Including oversight of all work performed under the IND

17. The Importance of Form FDA-1572
Statement of Investigator
Legally binding contract with FDA
Personally conduct study in accordance with protocol
Don’t make changes to the research without IRB approval
Promptly report any changes and unanticipated risks to IRB

18. Form FDA-3674
Certifies enrollment of referenced studies in clinicaltrials.gov
Refers to “applicable” clinical trials upon which the submission directly relies or which may not yet be published, not to literature references
Example: application uses data from a previous clinical trial to support going from Phase I to Phase II
Important: Make sure you have the appropriate information to complete this form. Willful and knowing false statements may be viewed as a criminal offense. 18 18

19. IND Application Approval Process
FDA Acknowledgment Letter
Arrives 1-2 weeks after FDA receipt of IND submission
Assigns IND number, gives date of receipt, reminds sponsor-investigator of obligations under the IND
NOT an approval to begin
May not start until 30 days after IND receipt date
Unless earlier notification indicates otherwise

20. Possible FDA Actions
Request additional information or place on clinical hold
Research cannot begin until all concerns are addressed in ways acceptable to FDA
Conclude project is exempt
Research may be conducted without an IND
Passive Activation
Allowing 30 days from filing to pass without comment
Helpful hint: Confirm FDA’s non-objection prior to starting any clinical trials.

21. Clinical Hold May apply to more than one study under an IND
Legal order to delay or suspend research
May apply to more than one study under an IND
May occur at the time of IND proposal or during clinical investigation
No new accrual
Existing participants may not receive study product
Source: 21 CFR

22. IND Post Approval Obligations
Selecting qualified investigators and monitors
Providing necessary information to investigators
Monitoring the research
Controlling the investigational product
Reporting significant adverse events to FDA, IRB, and investigators
Maintaining the IND
Maintaining and Retaining Accurate Records

23. Initiate National Protocol Registration
Register all research under the IND with clinicaltrials.gov
Contact the Clinical Trials Education Office (CTEO) for guidance or
More information: Topic covered in more detail in the National Protocol Registration module. 23 23 23

24. Manufacture and/or Label Investigational Product
Keep work areas clean and free of:
Dirt, dust, and vermin
Objects not required for manufacturing
Label drug(s) as follows:
Caution: New Drug—Limited by Federal [or United States] law to investigational use.
Source: 21 CFR 210, 312.6, 610

25. Select Qualified Investigators and Study Monitors
Base selection on training and experience
Obtain the following from participating investigators
Form FDA-1572
CV or other evidence indicating expertise in the clinical area of study
Source: 21 CFR

26. Provide Necessary Information to Investigators
Disseminate information with respect to adverse events and safe use of the investigational product
Protocol
Investigator’s brochure
Safety reports (SAEs, IND safety reports)
Progress reports
Publications
Source: 21 CFR

27. Train Participating Investigators
Train at the beginning and at intervals during the trial
Study protocol and study-specific procedures
Adverse event reporting
Protocol deviation and violation reporting
Establish procedures for training new investigators
Document protocol and study-specific training
Source: 21 CFR 27 27 27

28. Establish Regular Communications with Participating Investigators
Schedule progress reports with participating investigators
Suggested timelines
Weekly (phase I)
Monthly (phase II)
At least every 3-6 months (phase III)
Maintain documentation
Minutes from face-to-face meetings and teleconferences, or updates 28 28 28

29. Monitor the Research Adhere to the data and safety monitoring plan
Review the site monitoring reports for protocol and regulatory compliance
End participation of non-complying investigators
Discontinue shipments of study drug
Report serious non-compliance to FDA (and IRBs)
Source: 21 CFR

30. Control Distribution and Return of Investigational Product
Permit shipment of study product only to investigators participating in the study
Remind participating sites to return or properly destroy any unused investigational products
Maintain written records of the disposition
Source: 21 CFR

31. Evaluate Adverse Events (AEs)
Review safety and efficacy data as it is obtained from participating investigators
Identify all safety reports previously filed concerning a similar event
Analyze the significance of the event in light of previous similar reports
Determine if any corrective actions should be taken as a result of the event
Source: 21 CFR

32. Report Adverse Events to DFCI IRB
Report AEs and SAEs from any location
Use the appropriate internal or external event report form
Amend the protocol and/or revise the consent form as necessary
More information: General adverse event reporting is covered in more detail in the Monitoring Data and Participant Safety module.
Source: DF/HCC SOPs PM-402, PM-407, PM-408, AE-601 32 32 32

33. Report Adverse Events to FDA
Report via an IND Safety Report any AE that meets all three criteria:
Serious
Unexpected
Not in the drug brochure, protocol or consent form
Study treatment related
Report via an IND Safety Report all SAEs that are fatal or life-threatening
Associated with the use of the drug/biologic
Source: 21 CFR ; DF/HCC SOPs PM-408, AE-601 33 33 33

34. Report Events to Participating Investigators
Notify participating investigators of any event submitted to FDA
Provide same information submitted to FDA
Forward any DFCI IRB-approved corrective actions that must be taken as a result of the event
Amended protocol and/or revised consent form
Source: 21 CFR , ; DF/HCC SOPs PM-408, AE-601 34 34 34

35. Flow Of Adverse Event Reporting
Step 1:
Sponsor-Investigator
reviews all safety
information to
determine if any
event requires
expedited reporting
DFCI IRB
Sponsor-Investigator
FDA
Step 2:
Events requiring expedited reporting are
forwarded to DFCI IRB and FDA
Step 3:
SAEs and any corrective actions
are shared with participating
investigators
Local IRB A
Investigator A
Investigator B
Local IRB B 35 35

36. Summary of Adverse Event Notification
Who
Circumstance
Timeline
DFCI IRB
Reportable event from any study location
Within 10 days of notification
FDA
SAEs that are unexpected and related (or possibly related) to study
7-15 days from notification, depending on nature of event
Participating Investigators
After DFCI IRB review and response
Others
As appropriate
According to guidelines
Important: Reporting requirements for FDA or other oversight bodies may differ from the DFCI IRB. As Sponsor-Investigator, you must comply with all reporting requirements. 36 36 36

37. Maintain Accurate Study Records
Describe in writing all tasks delegated to others
Document the receipt, shipment, and disposition of the study product
Retain all study records in a secure facility
At least 2 years after study completion/discontinuation
For 6 years following study completion for HIPAA compliance
Helpful hint: Use the DF/HCC Delegation of Responsibility and Training Log available on the DF/HCC website under Clinical Research Unit.
Source: 21 CFR

38. Submit Records, Reports and Final Results
Allow authorized FDA representatives to have access to records/reports relating to the research
Submit safety and progress reports to FDA as required
Important information: Sponsor-investigators are obligated to allow FDA to inspect study conduct and documentation at any time. Contact QACT if your IND research is chosen for an FDA inspection.
Source: 21 CFR , , ; DF/HCC SOP OV-101

39. FDA Reporting Requirements under an IND
An IND is a living document
Protocol Amendments
Information Amendments
IND Safety Reports
Annual Reports
Final Study Report
Important information: Submit to FDA a new version of form 1571 with each amendment or report. Submit a new version of form 1572 with the appropriate protocol amendments.

40. Protocol Amendments
Notify FDA of any protocol changes under the IND as they are proposed and IRB approved
New protocol
Change to an existing protocol that affects:
Rights, safety or welfare of participants
Scope or scientific quality of the study
New investigator
Identify amendment contents
Example: “Protocol Amendment: New Protocol”
Source: 21 CFR

41. Changes to Existing Protocols that Require FDA Protocol Amendments
Increase in dose, duration of exposure, sample size
Addition/deletion of study group
New test or procedure to improve monitoring, reduce side effects or adverse events
Elimination of immediate hazard to study participants or tests that monitor safety

42. Information Amendments
Notify FDA of any other essential protocol information on the IND
Response to FDA comments
New toxicology, chemistry or technical information
Discontinuance of a study
Limit frequency to once every 30 days
Submit significant manufacturing changes in real time
Identify amendment contents
Example: “Information Amendment: Response ”
Source: 21 CFR

43. IND Safety Reports
Reporting serious and unexpected study-related AEs
Notify FDA of any AE associated with the study product that is both serious and unexpected
Include findings from tests in laboratory animals that suggest a significant risk to humans
Submit FDA Form 3500A or in narrative form
As soon as possible but no later than 15 calendar days from initial knowledge of the event
Notify all participating investigators
Source: 21 CFR

44. IND Safety Reports
Reporting unexpected fatal/life-threatening study-related AEs
Notify FDA of any unexpected fatal or life-threatening events related to the study product
Submit telephone and facsimile transmissions
As soon as possible but no later than 7 calendar days from initial knowledge of the event
Provide follow up information as soon as available
Notify all participating investigators
Source: 21 CFR 44 44

45. Annual Reports Submit to FDA within 60 days of IND anniversary
Brief report of the progress of the clinical investigation
Submit to FDA within 60 days of IND anniversary
Due each successive year
Report on status of each clinical study
Summarize data obtained in last year
Include IRB documentation
Helpful hint: Submit the IND Annual Report to FDA when filing the Continuing Review with DFCI IRB.
Source: 21 CFR

46. Final Study Report
Submit to FDA as soon as each clinical study concludes
No later than six months from study completion
Summarize results of each study as completely as possible

47. Discontinuation of an Investigation
When?
IND presents unreasonable or significant risk to participants
Submit an information amendment to FDA within 5 working days after determining the IND should be discontinued
Notify all participating investigators and IRBs
Source: 21 CFR 47 47

48. Withdrawal of an IND
May withdraw an effective IND at any time without prejudice
Submit an information amendment to FDA
Notify all participating investigators and IRBs
Source: 21 CFR 48 48

49. Summary of Periodic Submissions to FDA
Submission Type
Timeframe
Protocol Amendment: New Protocol
After IRB approval but before implementation
Protocol Amendment: Change in Protocol
Protocol Amendment: New Investigator
Within 30 days of being added
Information Amendments
At time of occurrence
IND Safety Report (serious & unexpected)
Within 15 calendar days of notice
IND Safety Report (fatal or life threatening)
Within 7 calendar days of notice
Annual Report
Within 60 days of anniversary
Discontinuation of investigation
Within 5 working days of decision
Withdrawal of IND

50. The Challenge
A sponsor-investigator must be aware of his or her responsibilities as the sponsor and attentive to the reporting standards of IND study conduct

51. Caveats about Undertaking Sponsor Investigator Trials
“Where problems have come in recent years, the majority have come in studies where the investigator was also the sponsor.”
David Lepay
FDA’s senior advisor on clinical science
Guide to Good Clinical Practice January 2005

52. Tales from FDA Warning Letters
Mistakes made by investigators acting as IND holders
You failed to submit an IND but followed subjects through August 2004 when you informed the IRB that the study was closed. 21 CFR (a)
As a sponsor, you failed to submit protocol amendments to the FDA before study revisions were implemented CFR (a) and (b)
No records available for any study monitoring prior to the monitoring report of xx. 21 CFR

53. How DF/HCC Can Help
Supply templates for investigator-initiated IND research
Initial IND submission template
IND annual report template
Various transmittal letter templates
Provide institutional contacts for IND-related questions
Assist with FDA audit preparation 53 53 53

54. For More Information Templates and Institutional Contacts
Contact the Clinical Trials Education Office (CTEO) or
FDA Audit Preparations
Contact the Quality Assurance Office for Clinical Trials (QACT) or
FDA Documents, Forms and Warning Letters
Refer to 54 54

55. Summary
There is only one code of federal regulations regarding IND research
FDA applies the same rules to every IND holder
Be familiar with your obligations under the IND
Seek guidance when necessary
Use DF/HCC and external resources to navigate the regulatory process and maintain an effective IND

56. Conclusion
Do I really want to hold an IND? If yes, then:
Be in charge of your project, give it your unswerving attention, and see it through to completion
Remember that absolute responsibility and accountability are required
Communication with all investigators and study teams is imperative
Monitoring and quality assurance are essential