investigational new drug (ind) orientation responsibilities of ind sponsor-investigators michr...

Investigational New Drug (IND) Orientation

Responsibilities of IND Sponsor-Investigators

MICHR IND/IDE Assistance Program (MIAP)


Definitions

• Sponsor is an individual, company, academic institution, or other organization that takes responsibility for and initiates a clinical investigation. The sponsor is not the “funding organization” by FDA definitions.

• Investigator is an individual under whose immediate direction a drug is administered or dispensed

• Sponsor-Investigator is an individual who both initiates and conducts an investigation. The requirements/responsibilities under this part include both those applicable to an investigator and a sponsor.


APPLICABLE REGULATIONS

The Federal Food, Drug, and Cosmetic Act (FD&CAct) gives the FDA authority to regulate drugs and biologics

Code of Federal Regulations (CFR)21 CFR Part 312: Investigational New Drugs

Contains procedures and requirements governing the use of investigational new drugs

Applies to all clinical investigations of products that are subject to section 505 of the FD&C Act

Website for INDs: IND Regulations

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/default.htm


Regulations

21 CFR §11 Electronic Records; Electronic Signatures

21 CFR §50 FDA (21 CFR) Protection of Human Subjects

21 CFR §54 Financial Disclosure by Clinical Investigators

21 CFR §56 Institutional Review Boards

21 CFR §58 Good Laboratory Practices

21 CFR §211, § 810 Good Manufacturing Practices

21 CFR §1271 Good Tissue Practices


Regulations

Investigational Application

21 CFR §312 IND Drugs and Biologics21 CFR §812 IDE Devices21 CFR §809 IVD In Vitro Diagnostics

Marketing Application

21 CFR §601 BLA Biologics21 CFR §314 NDA Drugs21 CFR §814 PMA Devices


Good Clinical Practice (GCP)

www.fda.gov/oc/gcp/

GCP is a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials.

Not Law, but FDA has adopted GCP.

(follow them…)

http://www.fda.gov/oc/gcp/


Conduct study in compliance with GCP, protocol, & applicable IND/IDE regulations

Ensure informed consent of each subject is obtained (and retained) Personally conduct or supervise the investigation Protect the rights, safety, and welfare of participants Ensure adequate medical care for the study participants Obtain necessary approvals from IRB Maintain and retain drug/device disposition and patient case history records Provide written reports to the IRB, as required Ensure changes are not implemented without prospective IRB/FDA approval Promptly report serious adverse events to the sponsor, IRB, and FDA Furnish Progress reports and Safety reports Ensure all study team members are informed about their obligations noted above

FDA RESPONSIBILITIES OF IND INVESTIGATORS


Submit necessary amendments/supplements to FDA

Ensure that FDA and all participating investigators are promptly informed of significant new adverse effects or risks

Maintain adequate records

Maintain proper control of the study drug/device

Select qualified investigators at other institutions for multi-site trials

Provide information to other investigators and study staff to ensure that the study is performed properly

Ensure proper monitoring of the study

Ensure the study is performed in accordance with the general investigational plan and protocol

FDA RESPONSIBILITIES OF IND SPONSOR-INVESTIGATORSIN ADDITION TO THE INVESTIGATOR RESPONSIBILITIES,SPONSOR-INVESTIGATORS ARE REQUIRED TO:


FDA Form 1571 (CFR 21 §312.23(a)(1)(i-ix))

• Contractual agreement between sponsor and FDA

• Contains name of person responsible for conduct and progress of the study (Item 15)

• Contains name of person responsible for the review and evaluation of information relevant to the safety of the drug (Item 16)

• Sponsor or sponsor’s authorized representative agrees to conduct investigation in accordance with all applicable regulatory requirements (Item 17)

FDA Form 1571


IND Maintenance (IND Amendments)

IND Amendment (Documents submitted to an active IND)

The 4 major types are…

• Protocol Amendments (21 CFR §312.30)• Information Amendments (21 CFR § 312.31)• IND Safety Reports (21 CFR § 312.32)• IND Annual Reports (21 CFR § 312.33)


Submission Timing

Amendment - New protocol After IRB approval

Amendment - Changed protocol At time of change, usually after IRB approval

Amendment - New investigator Within 30 days of being added

Amendment - Information At time of occurrence

IND safety report (unexpected AE that is serious and associated with the use of the drug or lab tests that suggest significant risk)

Within 15 calendar days of receiving notificationContact MIAP when you receive notification

IND safety report (unexpected fatal or life threatening experience associated with the use of the drug)

Within 7 calendar days of receiving notificationContact MIAP when you receive notification

Annual report Within 60 days of anniversary of IND

Withdrawal of IND At time of withdrawal

Discontinuation of investigation Within 5 working days of discontinuance

Financial disclosure report At time of change

FDA Submissions - Responsibilities To FDA


Amendments - New Protocol

• New study that is not covered by a protocol already contained in the IND

• Must submit the new protocol to the FDA• The new protocol can begin after both conditions have been

met:– The protocol has been approved by the IRB– The sponsor has submitted the protocol to the FDA for its review

• There is no need to wait for the 30 day review period at the FDA unless we have specifically asked the FDA for advice on the protocol content

• Contact MIAP early to discuss regulatory strategy


Amendments - Changes in a Protocol

• A sponsor shall submit a protocol amendment describing any change in a Phase I protocol that significantly affects the safety of subjects or any change in a Phase 2 or 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study

• Examples:– Any increase in drug dosage or duration of exposure of any individual

subjects– Any significant increase in the number of subjects under study– Any significant change in the design of a protocol (the addition or

dropping of a control group)– The addition of a new test, or procedure, that is intended to improve

monitoring for, or reduce the risk of, a side effect or adverse event; or the dropping of a test intended to monitor safety


Amendments – Changes in a protocol (continued)

• A protocol change may be implemented provided the following two conditions are met:– The change has been approved by the IRB with responsibility for

review and approval of the study– The sponsor has submitted the change to FDA for its review

• No need to wait 30 days unless we have specifically asked for feedback

• Contact MIAP early in process to discuss regulatory strategy– IRB Minor Amendment: URGENT REQUEST

• PLEASE contact MIAP immediately when starting this process


Amendments – Changes in Protocol (continued)

• Documents required to submit to the FDA– Summary of Changes Document for protocol– Tracked changed version of protocol– Clean version of protocol– Tracked changed version of informed consent document– Clean version of informed consent document


Amendments – New Investigator

• A sponsor shall submit a protocol amendment when a new investigator is added to carry out a previously submitted protocol

• The sponsor shall notify FDA of the new investigator within 30 days of the investigator being added

• Try to group new investigators/and or sites together• Also includes new lab, new clinic• Can submit together with a change in protocol or new protocol

submission• Required paperwork

– Form 1572– Investigator CV – signed and dated on first page

FDA Form 1572


Amendments – Information

• New toxicology, chemistry, or other technical information• New Investigator’s Brochure• Submit at the time of change, but, to the extent feasible, not more than

every 30 days• Can submit with protocol amendment or new investigator amendment


IND Safety Report

• Unexpected fatal or life threatening suspected adverse reactions– Must submit to the FDA within 7 calendar days of receiving the notification– Complete MedWatch 3500 A– Follow-up reports must be submitted as soon as possible

• Unexpected serious suspected adverse reactions– Must submit to the FDA within 15 calendar days of receiving the notification– Complete MedWatch 3500A

• Follow-up reports should be submitted within 15 days of receiving the first notification (not required if 7 day report is complete)

• If FDA requests any additional data or information, the sponsor must submit it to the FDA as soon as possible, but no later than 15 calendar days after receiving the request

• Contact MIAP if the IRB (at any site) disagrees with the Sponsor-Investigator assessment of attribution and causality

Safety Reporting Via MedWatch How to report

Patient/Subject

Product info(drug, biologic, device, etc.)

Description of Event or Problem

Reporter

Relevant tests/labs


Annual Report

• Due to the FDA within 60 calendar days of the IND Anniversary Date (date IND was deemed “safe to proceed”)

• MIAP will contact study coordinator and PI approximately 60 days before the report is due to obtain required information– Patient demographics– Study information (number of patients enrolled, number of sites, etc.)– Adverse events– Any other new information

• MIAP will complete the annual report template and send to study coordinator and PI to review

• MIAP will send final annual report to the FDA• Upload FDA annual report into eResearch application (ORIO)


• Clinical Trial Monitoring is required for clinical trials conducted under an IND

• Clinical Trial Monitor examines quality of trial conduct:– Perform on-site (if indicated, also off-site) evaluations of

trial-related activities– Identify deviations in protocol conduct– Review documents for Adverse Events– Drug accountability – see also handout of IDS monitoring

• Extent and frequency of monitoring as appropriate:– Length, complexity, subject enrollment and other aspects

of the trial

Monitoring the Trial


• Additional measure of human subject protection• Evaluates accumulating data from a clinical trial • Generally, established by the sponsor

– Select members, should be independent– Charter generally written by sponsor, may have consultation

by members• Recommendations regarding the conduct and design of the trial

(safety and efficacy)• Does not visit sites or substitute for clinical trial monitors• Send DSMB reports to the IRB for review

Monitoring the Trial: DSMB


The FDA Calls – now what?

• Make immediate internal notifications– IRB– Regulatory Affairs– MIAP

• Review UMHS Policy 01-01-020 “External/Third Party Reviews• IRBMED ORIO Reporting

– “As soon as possible after notification of the audit and prior to a site visit by an external oversight entity (e.g. sponsor, FDA). For FDA audits, you should also call the IRBMED Office

http://www.med.umich.edu/i/policies/umh/01-01-020.html


Most Common Violations Noted by the FDA

• Failure to follow the protocol

example: Required testing is incomplete

• Recordkeeping errors

• Informed consent problems/issues


Most Significant Violations noted by the FDA

• Enrollment of ineligible subjects• Violation of protocol affecting safety• Extensive data corrections and questionable changes • Inadequate oversight of study personnel

– Inappropriate delegation of authority– Poor oversight of sites

• No Informed consent• Failure to communicate with IRB


If you are doing something in eResearch then it may need to be reported to the FDA! Contact MIAP.

• Protocol deviations – dosing errors, safety reasons• Lapse in IRB Approval• Urgent Amendment request• Addition of new site• Adverse event


Add MIAP lead as a study team member in eResearch• Add as administrative staff• Question 1.6 NO to edit right• Question 1.7 YES to include this person on all correspondence


MIAP Established to Provide Comprehensive:

Regulatory Expertise…

Regulatory Support…

Regulatory Education Services…

To Faculty Investigators and their Team Involved In FDA Regulated

Clinical Research At The University of Michigan


MIAP SERVICES OVERVIEW• Agent/Device development strategy consultation• IND/IDE consultation including determination of need for IND or IDE• Pre-IND FDA meeting requests and support• Protocol development• IND/IDE application preparation and submission• Clinical hold response preparation/submission• Communication with the FDA, IRB and other regulatory bodies• IND/IDE “maintenance” support

– Safety report submissions– Protocol amendments to the FDA– Annual reports to the FDA

• Clinical Trial Monitoring– Investigators meetings– Site initiation visits– Interim site monitoring visits– Study close out activities


MIAP Activities FY 2012

• Supported 31 active INDs (representing 34 active clinical study protocols) and 2 IDEs

• Submitted 21 new IND applications and 2 new IDE applications to the FDA• Submitted 5 single-patient (expanded access) INDs and 2 emergency use

IDEs to the FDA• Submitted over 110 IND/IDE life-cycle maintenance submissions to the FDA• Submitted 10 IND exemption requests to the FDA• Submitted 3 pre IND/IDE meeting packages to the FDA


MIAP is here to help with INDs and IDEs

MIAP contacts:

Kevin Weatherwax, BS, CCRC, CCRAManager, MICHR IND/IDE Assistance Program (MIAP)Michigan Institute for Clinical and Health Research (MICHR)University of Michigan Health SystemNCRC Bldg # 4002800 Plymouth RoadAnn Arbor, MI 48109-2800Phone: 734-998-6275 Pager: 734-936-6266, #9912Fax: 734-998-7318Website: [email protected]

mailto:[email protected]


MIAP contacts (cont’d):

MICHR/MIAP CLINICAL RESEARCH PROJECT MANAGERS:

Mona Moore, MS, RAC Bill Reisdorph, MS, CQA, RACPhone: 734-998-7818 Phone: [email protected] [email protected]

Jeanne Wright, RN, BSN, MT, CCRP, RAC E. Mitchell Seymour, PhD, RACPhone: 734-998-7598 Phone: [email protected] [email protected]

MIAP TEAMShared group e-mail for documents:

[email protected]








Office of Human Research Compliance Review (OHRCR)

DirectorRon Maio, D.O., M.S., Professor, Department of Emergency [email protected] 734 647-0489

Research Compliance AssociatesTerry VandenBosch, PhD, RN, CIP, [email protected] 734 647-0457

Ted Hamilton, [email protected] 647-1622





UMMS Regulatory Affairs

Ray Hutchinson, MD, MS, Associate Dean734 615-1702 [email protected]

Pat Ward, MPA, [email protected]




Office of the General Counsel

Kara Morgenstern, JD, MPH, Assistant General Counsel

Phone: 734-763-6240

[email protected]

Institutional Review Board - IRBMED

Judith Birk, JD, IRBMED Director

Phone: 734-647-7615

Fax: 734-763-1234

[email protected]



Investigational Drug Service (IDS)

Helen Tamer, Pharm.D.

Clinical Pharmacist

Phone: 734-936-7469

Fax: 734-647-9302

[email protected]

Amy Skyles, Pharm. D.

Clinical Pharmacist

Phone: 734-936-8210

Fax: 734-936-7027

[email protected]

Drug shipment address:

University of Michigan Hospital

Department of Pharmacy Services-IDS

UH B2D400

1500 E. Medical Center Drive

Ann Arbor, MI 48109-0008

Attention: Investigational Drug Service




Labeling of Investigational Agents

21 CFR §312.6

• Immediate packaging of product – “Caution: New Drug – Limited by Federal (or United

States) law to investigational use”

• The labels and labeling shall not – Bear false and misleading statements– Represent that the drug is safe and effective for

purposes being investigated

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Q & A

investigational new drug (ind) orientation responsibilities of ind sponsor-investigators michr...

Documents

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participating investigators

dispensed sponsorinvestigator

fda definitions

fda authority

applicable indide regulations

nda drugs