Managing Sponsor/Investigator Relationships

1. Managing Sponsor/Investigator Relationships 5th National Conference on Managing Legal Risks in Structuring and Conducting Clinical Trials American Conference Institute Boston September 27, 2006 Michael A. Swit, Esq. Vice President, Life Sciences

2. Understand the Objectives of Each Party • Sponsor Objectives • Continued study of test article • Meet enrollment objectives • Obtain valid usable data • Investigator Objectives • Access to new therapies for patients • Prestige -- e.g., journal publications • Supplement income 2

3. Understand the Responsibilities of Each Party Sponsor Responsibilities • Develop Protocol and Investigational Plan • Select Qualified Investigators • Provide investigator with Investigator Brochure (Update as necessary) • Maintain Effective IND 3

4. Understand the Responsibilities of Each Party Sponsor Responsibilities (cont.): • Monitor Investigations to assure compliance with protocol, investigational plan, and FDA requirements • Data Review for safety and efficacy • Notify FDA and Investigators about significant new adverse effects or risks 4

5. Understand the Responsibilities of Each Party Sponsor Responsibilities (cont.) – Maintain required records – Study Drug control documentation – Investigator financial interest – File required reports with FDA: -Annual Report -IND Safety Reports 5

6. Understand the Responsibilities of Each Party Sponsor Responsibilities (cont.) • A sponsor who discovers investigator noncompliance with the signed agreement (form FDA -1572), the investigational plan, or any applicable FDA regulation shall promptly secure compliance or discontinue shipment of the investigational new drug to the investigator and end that investigator’s participation in the study. The sponsor shall notify FDA when an investigator is no longer participating in the study. 21 C.F.R. 312.56. 6

7. Understand the Responsibilities of Each Party Investigator Responsibilities • Complete Financial Disclosure Information and update as necessary • Complete and sign Form 1572 • Comply with Commitments • Conduct study in accord with protocol, • Only make changes to protocol after notifying sponsor, and with IRB approval, except when necessary to protect safety, rights, or welfare of subjects 7

8. Understand the Responsibilities of Each Party Investigator Responsibilities (cont.) • Comply with Commitments (cont.): • Comply with all FDA requirements • Personally conduct or supervise the investigation • Comply with informed consent and IRB requirements • Report adverse experiences to sponsor and IRB • Read and understand investigator brochure • Assure that those assisting in study are informed about their obligations to meet these commitments 8

9. Understand the Responsibilities of Each Party Investigator Responsibilities (cont.) • Comply with Commitments (cont.) • Comply with informed consent and IRB requirements • Report adverse experiences to sponsor and IRB • Read and understand investigator brochure • Assure that those assisting in study are informed about their obligations to meet these commitments 9

10. Understand the Responsibilities of Each Party Investigator Responsibilities (cont.) • Control Investigational New Drug • Prepare Records • Prepare adequate and accurate case histories • Case report forms and supporting data • Informed consent • Medical records 10

11. Understand the Responsibilities of Each Party Investigator Responsibilities (cont.) Reports • Progress Reports (at least annually) • Safety Reports • Prompt report to sponsor of any effect that may reasonably be regarded as caused by, or probably caused by the study drug. Report alarming adverse effect immediately. • Final Report • At end of study, provide sponsor with a report discussing the investigator’s participation in the study. 11

12. Understand the Responsibilities of Each Party Investigator Responsibilities (cont.) • Maintain all records for a period of 2 years following the date a marketing application is approved, or if no application is filed or approved, 2 years after the investigation is discontinued and FDA is notified (21 CFR 312.62(c) 12

13. Understand the Responsibilities of Each Party Other Investigator Responsibilities • HIPAA Compliance • Reimbursement Compliance 13

14. Trouble in Paradise: What can happen when things go wrong FDA Inspection Authority • Inspection of clinical research records & reports at reasonable times. • 21 C.F.R. 312.68 - Investigator • 21 CFR 312.58 - Sponsor 14

15. Trouble in Paradise: What can happen when things go wrong FDA Enforcement Measures • Public Notice (Policy Response) • Notice of Violation • FDA Warning Letters • Investigator Disqualification • 21 C.F.R. 312.70 • Repeated or deliberate failure to comply with applicable FDA regulations, or submission of false statements to FDA or sponsor in any required report 15

16. Trouble in Paradise: What can happen when things go wrong FDA Enforcement Measures (cont.) • Debarment • Generic Drug Enforcement Act of 1992 (Debarment Act); 21 U.S.C. § 355a • Bars a person from providing any services to companies with approved or pending NDAs or ANDAs • Historically applied to employees of pharmaceutical company 16

17. Trouble in Paradise: What can happen when things go wrong FDA Enforcement Measures (cont.) Application Integrity Policy • FDA Compliance Policy Guide 7150.09 (July 1, 1999) • FDA will conduct investigations to identify all instances of fraud or wrongful acts 17

18. Trouble in Paradise: What can happen when things go wrong Criminal Prosecution • Federal Food, Drug, and Cosmetic Act Violation • Federal Violations (felony) False Statements Wire Fraud Mail Fraud Conspiracy 18

19. Trouble in Paradise: What can happen when things go wrong Congressional Investigations • Constitutional Authority: McGrain v. Daugherty, 273 U.S. 135 (1927) Congress may conduct investigations to further its legislative function pursuant to Article 1 of the United States Constitution • Rules of Engagement • Title II of the United States Code • Standing Rules of the Senate, Rule XXVI, Committee Procedure • Rules of the House, Rules X and XI 19

20. Trouble in Paradise: What can happen when things go wrong Senate Committee on Finance (Recent Activity) • Investigation of sponsor funding of research • Investigation of sale by clinical researchers of drug-study secret • Investigation of human subject protections at clinical research site 20

21. Measures to Increase Compliant Collaboration/Decrease Liability 1. Assure Detailed and Complete • Clinical Trial Agreement -- use to regulate the relationship • Key issue – financial disclosure re conflicts • Protocol – both initial and amendments – ensure amendments are communicated effectively and, if needed, with training • Investigator’s Brochure 21

22. Measures to Increase Compliant Collaboration/Decrease Liability • Require Investigator Training ** GCP ** Product – especially important for devices 3. Require Standard Operating Procedures 22

23. Measures to Increase Compliant Collaboration/Decrease Liability 4. Conduct Investigator Due Diligence: • Check FDA databases for disqualified and debarred investigators • Check FDA’s NIDPOE database • Check FDA Warning Letter database • Check HHS Office of Research Integrity’s database for Research Misconduct Cases • Check/PHS Actions/Debarment Actions database • FOIA FDA inspection documents on investigators • Check State Licensing Board to verify current Medical License • Google!!! 23

24. Measures to Increase Compliant Collaboration/Decrease Liability 5. Employ an Effective Monitoring Program • Pre-Study Visit • Study Initiation Visit • Periodic Visits • Closeout Visit • Monitor your Monitors • Monitor your CRO if you have one • Follow up on deficient monitoring visits 24

25. The End

26. About the speaker … Michael A. Swit, Esq., who is Vice President, Life Sciences at THE WEINBERG GROUP INC., has extensive experience in all aspects of FDA regulation with a particular emphasis on drugs and medical device regulation. In addition to his private legal and consulting experience, Mr. Swit also served for three and a half years as vice president and general counsel of Pharmaceutical Resources, Inc. (PRI) a prominent generic drug company and, thus, brings an industry and commercial perspective to his representation of FDA-regulated companies. While at PRI from 1990 to late 1993, Mr. Swit spearheaded the company’s defense of multiple grand jury investigations, other federal and state proceedings, and securities litigation stemming from the acts of prior management. Mr. Swit then served from 1994 to 1998 as CEO of Washington Business Information, Inc. (WBII) a premier publisher of FDA regulatory newsletters and other specialty information products for the FDA publishing company. Before joining THE WEINBERG GROUP, he served in the FDA Regulatory Law Practices at both Heller Ehrman and McKenna & Cuneo, first in that firm’s D.C. office and then in its San Diego office. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius from 1984 to 1988. Mr. Swit has taught and written on a wide variety of subjects relating to FDA law including, since 1989, co-directing a three-day intensive course on the generic drug approval process, serving on the Editorial Board of the Food & Drug Law Journal, and editing a guide to the generic drug approval process, Getting Your Generic Drug Approved, published by WBII. Mr. Swit holds an A.B., magna cum laude, with high honors in history, in 1979, from Bowdoin College, and earned his law degree from Emory University in 1982. He is a member of the California, Virginia and District of Columbia bars. 26

27. Questions? Call, e-mail, fax or write: Michael A. Swit, Esq. Vice President, Life Sciences THE WEINBERG GROUP INC. 336 North Coast Hwy. 101 Suite C Encinitas, CA 92024 Phone 760.633.3343 Fax 760.633.3501 Cell 760.815.4762 D.C. Office 202.730.4123 michael.swit@weinberggroup.com www.weinberggroup.com 27

28. For more than twenty years, leading companies have depended on THE WEINBERG GROUP when their products are at risk. Our technical, scientific and regulatory experts deliver the crucial results that get products to market and keep them there. Washington, D.C. ♦ San Francisco ♦ Brussels 28