Investigator and Study Coordinator Responsibilities: A Focus on FDAs Final Guidance

1. Investigator and Study Coordinator Responsibilities: A Focus on FDAs Final Guidance Kimberly Summers, PharmD Deputy ACOS for Research South Texas Veterans Health Care System Research & Development Service

2. FDA Responsibilities • FDA has responsibility for clinical investigations of FDA-regulated products • Irrespective of study funding (unlike OHRP) • Irrespective of study location within the U.S. • Irrespective of whether for commercialization/marketing or for scientific knowledge

3. Investigator Responsibilities for FDA Regulated Research • Protecting the rights, safety, and welfare of subjects under the investigator’s care • Ensuring clinical investigation is conducted according to • Good Clinical Practice (GCP) • the investigational plan (protocol) • signed investigator statement (1572) • Controlling drugs, biological products, and devices under investigation

4. FDA Final Guidance on Investigator Responsibilities • Drafted in 2007 • Issued in final form October 2009 • Intended to clarify FDA expectations with regard to investigator’s responsibility • To protect the rights, safety, and welfare of study subjects • To supervise a clinical study in which some study tasks are delegated

5. Subject’s Health, Safety, and Welfare • Human Subjects Protection • Protect human subjects during a clinical trial • Protect patients who may take product in the future, once product is approved 21 CFR 312.60 and 812.100

6. PI Responsibilities For Ensuring Human Subjects Protections • Providing reasonable medical care • Providing reasonable access to needed medical care • Adhering to the protocol

7. Providing Reasonable Medical Care • Ensure all adverse events related to study participation receive adequate medical care • Refer to a qualified practitioner if the PI lacks the expertise to provide the care needed • Provide treatment until resolution even if follow-up extends beyond the end of the study • Inform subjects when medical care is needed for conditions unrelated to study intervention if identified through screening procedures (incidental findings)

8. Incidental Findings In Research • Subject’s primary care provider should be notified • Communication with primary care provider should be documented in CPRS • PI should assist subject in obtaining medical care if no primary care provider is available

9. Providing Reasonable Access to Medical Care • Either by the investigator or another qualified individual • Availability 24 hours a day • Investigator within reasonably close proximity • Delegated responsibility to a specific qualified individual if PI is unavailable for a period of time • Study subjects should be educated on possible need for contact and how to obtain it • If PI in a non-physician, adequate provision for any necessary medical care by a physician must be in place

10. Adhering to the Protocol • Non-compliance with the protocol may be considered a failure to protect the rights, safety, and welfare of subjects • Study subjects may be exposed to unreasonable risks • Failure to adhere to inclusion/exclusion criteria • Failure to perform safety assessments • These risks are minimized by adhering to the protocol

11. Ensuring clinical investigation is conducted according to • Good Clinical Practice (GCP) • The investigational plan (protocol) • Signed investigator statement (1572)

12. Following Good Clinical Practice (GCP) • A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that • Rights, Integrity, and Confidentiality of Trial Subjects are Protected. • Data and Reported Results are Credible, and Accurate = Ethics = Quality Data

13. Following Investigational Plan • Maintain adequate and accurate case histories • Obtain informed consent • Maintain adequate records of the disposition of the drug • Submit required reports to IRB and sponsor • Adhering to inclusion/exclusion criteria • Following data safety and monitoring plan

14. Adhering to Statement of Investigator • An agreement signed by the investigator to provide certain information to the sponsor and assure that he/she will comply with FDA regulations related to the conduct of a clinical investigation of an investigational drug or biologic. • Form 1572 • Investigator Commitments: Box 9

15. Small Print of the 1572 • Supervise • Maintain adequate records (including drug disposition) • Adhere to protocol • Learn the Investigator Brochure • Let regulatory authorities inspect • Performance review (study staff and staff not directly employed if applicable) • Report adverse events • Inform subjects • Notify the IRB • Train staff

16. Supervision of Delegated Tasks: FDA Warning Letters • “People issues” are noted often in the warning letter: • “Not qualified” “inexperienced” “unauthorized” • Need to “supervise” “monitor” “train” S M A L L P R I N T [of the FDA Form 1572]

17. Noncompliance With GCP • “These errors reflect a pattern of insufficient training and experience that may impact the safety and welfare of subjects, and the ability to determine the safety and efficacy of the study drug.” ethics data quality

18. PI Delegation • The investigator who delegates tasks related to the research is responsible for providing adequate supervision to whomever the task is delegated and is accountable for regulatory violations caused from failure to supervise the conduct of the study

19. FDA Focus in Assessing Adequacy of Supervision • Are individuals delegated tasks qualified to perform such tasks • Are study staff receiving adequate training on delegated duties and the protocol • Is adequate supervision and involvement in the ongoing conduct of the study present • Is there adequate supervision and oversight of any third parties

20. Delegation of Study-Related Tasks • Ensure individual to whom task delegated is qualified by education/training/experience to perform delegated task • Appropriate delegation usually an issue for tasks that are clinical/medical in nature • May also require formal training and/or licensing/certification requirements that may vary by state • Qualified = competent to perform • Screening evaluations, PE, Assessment of primary endpoints, evaluation of adverse events, obtaining informed consent

21. Protocol Requirements • If protocol states a specific individual is to perform certain protocol required tasks • Protocol must be followed • Even if state law may permit different qualified staff to perform • Example: NP able to perform PE under physician supervision by state law, however, if protocol states PE must be done by MD

22. Inappropriate Delegation: FDA Warning Letters • Screening evaluations, including obtaining medical histories or assessment of inclusion/exclusion criteria, performed by individual with inadequate medical training (e.g. medical assistant) • Informed consent obtained by individuals who lack the medical training, knowledge of protocol, or familiarity with investigational product needed to discuss risk/benefits of clinical trial with prospective subjects

23. Goals of Adequate Training • Ensure staff have: • General familiarity with study/protocol • Specific understanding of details of protocol relevant to their tasks • Competency to perform tasks which they have been delegated • Awareness of regulatory requirements/acceptable standards for conducting research, related to both conduct of clinical trial and human subject protection • Information on changes during research with additional training if appropriate

24. Adequate Training Documentation • Allow for possibility of staff turnover and plan to ensure training for replacement staff • Keep list of appropriately qualified persons to whom significant trial-related duties have been delegated • Specify delegated tasks • Identify training individual received • Record dates of study involvement • Should have a separate delegation list for each study • Establish procedure for reviewing the performance of delegated tasks in timely manner • Ensure delegated tasks are consistent with Scope of Practice

25. Adequate Supervision of the Conduct of an Ongoing Clinical Trial • Should have detailed plan for supervision and oversight which includes the following elements: • Routine meetings with staff to review progress and updates • Procedures for ensuring staff compliance with protocol, and adverse event assessment and reporting • Having subinvestigators, if appropriate or necessary • Elements should be documented

26. Adequate Supervision: Warning Signs • Inexperienced/overburdened study staff • Complex clinical trials, and a large number of subjects enrolled • Conducting a large number of studies at the same time • Conducting research from a remote (off-site) location • Study conducted at multiple sites under the supervision of a single investigator (especially if sites geographically separated)

27. Investigator’s Responsibilities for Oversight of Third Parties • Study staff not in investigator’s direct employ • Investigator still supervises study tasks performed by this staff • Investigator must ensure adequate training has been completed • Investigator must provide training if not previously provided • Parties other than study staff • Critical aspects of study performed by those not involved directly in patient care/contact, and not under control of investigator • If sponsor retains services, the sponsor is responsible for ensuring these parties are fulfilling their study responsibilities • If the PI retains the services, the PI is responsible for ensuring these parties are fulfilling their study responsibilities

28. FDA Warning Letters • In 2009 FDA issued warning letters at the rate of one-and-a-half per day • 23% increase over 2008 • Clinical trial regulations were the subject of more than 20 warning letters in 2009.

29. Richard Borison, PhD and Bruce Diamond, MD Case • Investigators at the Medical College of Georgia • Hired inexperienced study coordinators • FDA inspection Nov 1996 – Apr 1997 • 20 significant finding against Dr. Borison • 13 significant finding against Dr. Diamond

30. Wall Street Journal Headlines • Drug Makers Relied on Clinical Researchers Who Now Await Trial • Two Professors are Accused of Endangering Patients and Stealing $10million • ‘Checks and Balances’ Failed

31. Inappropriate Delegation to Study Coordinators • “Two of their study coordinators had been hired after working as Girl Scout administrators; another had recently been a Delta Airlines flight attendant.” • Ms. A “who began working … as a study coordinator …, also had no medical training, yet was put to work interpreting electrocardiograms and blood tests. WSJ: 15 Aug 1997

32. Inappropriate Supervision of Coordinators • Ms. B “who coordinated Borison-Diamond drug trials at the VA hospital says Dr Diamond pushed her so to hard to recruit and retain subjects for a Sandoz study of a schizophrenia drug that she misled patients – claiming the experimental medicine may be the “next wonder” drug.” WSJ: 15 Aug 1997

33. Results of FDA Investigation

34. Robert Fiddes, MD Case • Southern California Research Institute • Conducted more than 170 studies for the pharmaceutical industry • Accused of research fraud and inadequate oversight and monitoring

35. Inexperienced Study Coorindators • “Few employees other than the study coordinators – mostly women of limited financial means – aware of the magnitude of the swindle.” • “Like every other study coordinator who passed through Dr. Fiddes’s research center, Ms. C found herself being pushed to break the rules.” NYT: 17 May 1999

36. Inappropriate Actions of Study Coordinators with Delegated Duties • “Again and again, study coordinators were instructed by Dr. Fiddes and his top aide, Ms. Charpentier, to ignore the requirements of the drug studies.” • “Dr. Fiddes’s coordinators, paid bonuses for recruiting patients into studies, soon began improperly enrolling themselves and members of their families.” NYT: 17 May 1999

37. Dr. Fiddes Defense • “…Dr Fiddes laid much of the blame for everything that happened on his study coordinators – again, without providing evidence to support the assertion.” • “He told them that fraud was rampant in the research industry. He named names of doctors he suspected of engaging in practices similar to his own.” NYT: 17 May 1999

38. Who’s Responsible • Dr. Fiddes • Sentenced to 15 months in prison • Ordered to repay $800,000 • Debarred • 3 study coordinators were also found guilty • One study coordinator was debarred.

39. Inadequate Government and Sponsor Monitoring? • “But, the investigators asked, …What could the watchdogs have seen that would have allowed them to detect his fraud? • “Nothing, Dr Fiddes replied. ” • “Had it not been for a disgruntled employee, he would have still been in business.” • Disgruntled employee was a study coordinator NYT: 17 May 1999

40. FDA Timeline for Dr. Fiddes

41. FDA Inspections- Triggered by Investigator Action • “You stated that you were not provided with a specific chart by the sponsor to determine exclusion. As a result, this issue was overlooked at the time of the consent. This response is inadequate because as a clinical investigator, it is your responsibility to follow the protocol, including its exclusion criteria. • “You stated that the unapproved versions of the informed consent forms had a much clearer description of the PURPOSE OF THE STUDY. This response is not adequate. . . . It is your responsibility to use informed consent forms that have been approved by the reviewing IRB prior to initiating any study related procedures.”

42. Final Advice • Conduct “ethical” clinical research • Protect the “needs of” and “risks to” patients • Generate “quality data” • Follow “GCP responsibilities” of the 1572 • Develop strong partnerships between investigator and study coordinator • Develop, implement, and monitor well written Standard Operating Procedures (SOPs)

43. Questions? Kimberly Summers, PharmD Office: (210) 617-5300 ext 15969 Email: kimberlyk.Summers@va.gov