1. FDA Draft Guidance on the Form FDA 1572 --- and Other Updates David A. Lepay, M.D., Ph.D. Senior Advisor for Clinical Science, U.S. FDA DIA GCP All-SIAC Teleconference September 25, 2008

2. Form 1572: Frequently Asked Question (FAQ) Draft Guidance  Why this guidance ?  FDA continues to receive a very large number of queries --- both domestic and international --- about the Form 1572  How to access the draft guidance ?  Available on-line at  http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA- 2008-D-0406-gdl.pdf http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA- 2008-D-0406-gdl.pdf  Also available through link from FDA’s GCP website: www.fda.gov/oc/gcpwww.fda.gov/oc/gcp

3. Form 1572: Frequently Asked Question (FAQ) Draft Guidance  When did the draft guidance issue ?  July 29, 2008  What is meant by “draft” guidance ?  Issued for public comment (comment period to September 29, 2008)  FDA plans to issue final version following review of public comments: will then represent FDA’s current thinking on the topic

4. Form FDA 1572: What It Is (FAQ 1)  Form 1572 = Statement of Investigator  Required of the study sponsor from each clinical investigator operating under a U.S. IND (see 21 CFR 312.53(c))  Agreement  Signed by the investigator  To provide certain information to the sponsor  And to assure that the investigator will comply with FDA regulations  For conduct of a clinical investigation of an investigational drug or biologic

5. 1572: Accessing the Form  Form is available on-line at  www.fda.gov/opacom/morechoices/fdaforms/ FDA-1572.pdf www.fda.gov/opacom/morechoices/fdaforms/ FDA-1572.pdf

6. Purposes of the 1572 -1- : Informational to the Sponsor  Identification of the investigator (name and address): Block 1  Information about the investigator’s qualifications: Block 2 and attached CV or other statement of qualifications  Enables sponsor to establish and document that the investigator is qualified  Information about the clinical site: Blocks 3-6  Enables sponsor to establish/document that the site is an appropriate location to conduct the study

7. Purposes of the 1572 -2- : Commitment to the Sponsor  Inform the investigator of his/her obligations and obtain the investigator’s commitment to follow pertinent FDA regulations for the subject study(ies)  Identification [name and code number, if any] of and protocol information about the subject study(ies): Blocks 7 and 8  Investigator commitments: Block 9  Investigator’s signature/date: Blocks 10 and 11

8. Does the 1572 Need to Be Submitted to FDA ? (FAQ 6)  No. Although the sponsor is required to collect the 1572 from the investigator, FDA does not require the form to be submitted to the agency  However many sponsors do submit the 1572 to FDA

9. Whether the 1572 Is or Is Not Submitted to FDA….  The 1572 facilitates collection of information that the sponsor is otherwise required to submit to FDA in an IND or NDA application  For example per 21 CFR 312.23(a)(6)(iii)(b), a protocol is required to contain the following  “The name and address and a statement of the qualifications…of each investigator, and the name of each subinvestigator…working under the supervision of the investigator; the name and address of the research facilities to be used; and the name and address of each reviewing Institutional Review Board”

10. When Must This Form Be Completed/Signed ? (FAQ 3)  Before sponsor permits investigator to begin participation in a clinical study  After investigator has enough information to be informed about the study and understand the commitments in Block 9  Received, read and understands the  Investigator’s Brochure  Protocol  Familiar with FDA regulations governing the study

11. Accurate Completion of the 1572 (FAQs 2 and 3)  Investigator should complete the form as accurately as he/she can  Investigator’s signature is affirmative assertion he/she is qualified to conduct the study and constitutes the investigator’s commitment to abide by FDA regulations in conducting the study  Making a willfully false statement is a criminal offense and can be taken into consideration in a disqualification proceeding

12. Updates to Information on the 1572 (FAQ 7)  Investigator should document the changes in the study record and inform the sponsor of these changes  Sponsor: Should appropriately update the IND  1572 itself does not need to be revised and a new 1572 need not be completed

13. Investigator Qualifications (FAQs 4 and 5)  FDA regulations do not require that the clinical investigator (CI) be a physician  If non-physician, qualified physician (or dentist, as appropriate) should be listed as a subinvestigator  Sponsors have discretion in determining CI qualifications to conduct the study  CI must be qualified as appropriate expert to investigate the drug  Regulations don’t specify minimum qualifications  Would include general familiarity with human subject protection and GCP requirements

14. Is 1572 Required for Non-IND or Medical Device Studies ? (FAQ 8)  No.  Only required for studies of investigational drugs and biologics conducted under an IND  Sponsors of device studies must obtain a signed investigator agreement from each investigator  Information is similar to that requested on the 1572  But 1572 is not applicable to investigational device studies

15. Non-U.S. Studies/Study Sites  Addressed in FAQs 8-13  Important to also reference FDA’s recent final rule: 21 CFR 312.120, Foreign Clinical Studies Not Conducted Under an IND  Issued 4/28/08 with effective date of 10/27/08  Available at: http://www.regulations.gov/fdmspublic/component/ main?main=DocumentDetail&o=0900006480537f08 http://www.regulations.gov/fdmspublic/component/ main?main=DocumentDetail&o=0900006480537f08  And 21 CFR 314.106, Foreign Data

16. Non-U.S. Clinical Studies -1-  No requirement to conduct a non-U.S. study under an IND  Sponsor may choose to do so  In this case, all FDA IND requirements must be met unless waived  This includes the requirement to obtain a signed 1572 from each investigator

17. Non-U.S. Clinical Studies -2-  Non-U.S. clinical study NOT conducted under an IND  Must comply with 21 CFR 312.120 if the sponsor intends to submit the study to FDA to support other IND clinical studies or to support marketing approval (NDA)  For a non-U.S. non-IND study, no 1572 is required from investigator(s)

18. Non-U.S. Clinical Studies -3-  For a non-U.S. study conducted under an IND, how can an investigator sign the 1572 when he/she knowingly cannot commit to all of the requirements on the form, specifically IRB membership ?  Waiver provision for IRB requirements  Waiver must be prospectively requested by the sponsor and granted by FDA  Request should contain a description of alternative mechanisms for assuring subject protection (e.g., ICH E6)

19. Non-U.S. Clinical Studies -4-  (NOTE: Where local/national laws impose additional requirements exceeding FDA regulations, FDA expects compliance with those local/national laws)

20. Non-U.S. Study Sites in a Study with U.S. Sites -1-  Must non-U.S. sites in a multinational study that includes U.S. sites be conducted under an IND ?  No…  U.S. sites must be conducted under the IND  Sponsor may choose, but is not required, to include the non-U.S. clinical sites under the IND (1572 is then required)  Sponsor may alternatively chose not to include the non-U.S. sites under the IND

21. Non-U.S. Study Sites in a Study with U.S. Sites -2-  Non-U.S. sites which the sponsor has chosen not to include under the IND  1572 not required from investigators at these sites  Protocol for these sites does not need to be submitted to the IND  However, if the intent is to pool the data from U.S. and non-U.S. sites, the protocols would ordinarily be very similar or identical  FDA recommends discussing (in advance with the appropriate review division) plans to pool data

22. Non-U.S. Study Sites in a Study with U.S. Sites -3-  Certain safety reporting requirements must be met regardless of whether the non-U.S. study sites are operated as IND or as non-IND sites  Sponsor requirement to review information about the safety of the investigational drug from any source, foreign or domestic (21 CFR 312.32(b))  Sponsor requirement to notify FDA and all participating investigators in a written safety report of any serious and unexpected adverse experience associated with use of the drug (21 CFR 312.32(c))

23. Back to the Form 1572 Itself…  OMB Expiration Date on the form (FAQ 14)  No need to prepare and sign a new 1572 when this date is reached  Two-page vs. double-sided form (FAQ 15)  Either is acceptable; best to staple if two-page  Form may be completed by hand (FAQ 16)

24. Name and Address of Investigator (Block #1)  Use investigator’s legal name (FAQ 17)  Use investigator’s official address of record (FAQ 18)  Co-investigators should not be listed in Block #1 (FAQ 19)  “Co-investigator” is not defined in FDA regulation  Acceptable to have more than one investigator (fulfilling ALL regulatory obligations of an investigator) at one site  Each is an investigator; must sign a separate 1572

25. CV/Statement of Qualifications (Block #2)  Information identified in this block and attached to the 1572 enables the sponsor to assess an investigator’s qualifications (FAQ 20)  FDA regulations do not require a CV/statement of qualifications to be updated during a study (FAQ 21)  FDA regulations do not require a CV to be signed and dated (FAQ 22)

26. Research Facilities (Block #3)  Address where the investigation will be conducted and where the test article will be shipped, if different from CI’s address of record (FAQ 23)  Facilities where subjects will be seen and study procedures performed; facilities where other important study functions are performed (FAQ 24)  If CI sees subjects at more than one site, list each of the sites (FAQ 25)  If protocol allows for home administration of test article, study records should reflect this, but subjects’ home addresses do not have to be listed (FAQ 26)

27. Clinical Laboratory Facilities (Block #4)  Labs or testing facilities directly contributing to or supporting the clinical trial (FAQ 27)  If central lab sends samples to its own satellite labs for additional testing: only necessary to list the central lab (FAQ 28)

28. IRB (Block #5)  IRB need not be at the same location as where the research is performed (FAQ 29)  FDA regulations allow independent or non- institutional IRBs and use of a cooperative IRB review process  Investigator commits to initial and continuing review and approval by an IRB that is in compliance with 21 CFR Part 56 (see Commitments, Block #9)

29. Subinvestigator(s) (Block #6) -1-  Who should be listed as a subinvestigator (FAQ 30)  Part of the investigative team  Performs significant study-related duties  Makes a direct and significant contribution to the data  “In general, if an individual is directly involved in the treatment or evaluation of research subjects, that individual should be listed on the 1572”

30. Subinvestigator(s) (Block #6) -2-  To list or not to list ? (FAQ 31)  Hospital staff (including nurses, residents or fellows and office staff) who provide ancillary or intermittent care but NOT a direct and significant contribution to the data: Do not list individually  Where staff residents on rotation participate in the study: include a general statement regarding their planned participation

31. Subinvestigator(s) (Block #6) -3-  To list or not to list ? (FAQ 32)  Pharmacist  Dispensing tablets but no responsibility for evaluating or reporting data: Do not list  If compounding, labeling, monitoring and reporting test article compliance data: Appropriate to list  Research Coordinator  Only transcribing data and maintaining files: Do not list  Performing critical study functions and collecting/ evaluating data: Appropriate to list

32. Subinvestigator(s) (Block #6) -4-  1572 does not require a CV/statement of qualifications for subinvestigators (FAQ 33)  Subinvestigators listed in Block #6 are required to submit information about their financial interests under 21 CFR Part 54 (FAQ 34)  For purposes of this financial disclosure regulation, also includes the spouse and each dependent child of the subinvestigator

33. Any Other Questions About the Form FDA 1572  Check the file of redacted replies to GCP questions submitted to FDA by the public  www.fda.gov/oc/gcp, link to “GCPP E-Mail Replies” and then to “FDA Forms 1571 and 1572” www.fda.gov/oc/gcp  Submit your question to:  gcp.questions@fda.hhs.gov or gcp.questions@fda.hhs.gov  druginfo@fda.hhs.gov druginfo@fda.hhs.gov