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

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

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

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

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

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)

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)

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)

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

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

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

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

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

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

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.

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

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

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

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

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.

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 312.42

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

Initiate National Protocol Registration Register all research under the IND with clinicaltrials.gov Contact the Clinical Trials Education Office (CTEO) for guidance cteo@dfci.harvard.edu or 617-582-8480 More information: Topic covered in more detail in the National Protocol Registration module. 23 23 23

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

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 312.53

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 312.55

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 312.55 27 27 27

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 email updates 28 28 28

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 312.56

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 312.59

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 312.32

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

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 312.32; DF/HCC SOPs PM-408, AE-601 33 33 33

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 312.32, 312.55; DF/HCC SOPs PM-408, AE-601 34 34 34

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

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

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 312.59

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 312.30-312.33, 312.38, 312.58; DF/HCC SOP OV-101

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.

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 312.30

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

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 312.31

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 312.32

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 312.32 44 44

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 312.33

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

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 312.56 47 47

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 312.38 48 48

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

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

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

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 312.20(a) As a sponsor, you failed to submit protocol amendments to the FDA before study revisions were implemented. 21 CFR 312.30 (a) and (b) No records available for any study monitoring prior to the monitoring report of xx. 21 CFR 312.50

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

For More Information Templates and Institutional Contacts Contact the Clinical Trials Education Office (CTEO) cteo@dfci.harvard.edu or 617-582-8480 FDA Audit Preparations Contact the Quality Assurance Office for Clinical Trials (QACT) qcc@dfci.harvard.edu or 617-632-3761 FDA Documents, Forms and Warning Letters Refer to www.fda.gov 54 54

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

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