“Good Clinical Practices” in Meeting Regulatory Responsibilities

1. “Good Clinical Practices” in Meeting Regulatory Responsibilities Terry VandenBosch, RN, PhD, CIP, CCRP Senior Research Compliance Associate Office of Human Research Compliance Review University of Michigan September 15, 2010

2. Today’s Discussion • Discuss the growing field of “regulatory science” • Describe responsibilities of FDA sponsor-investigators • Contrast ethical principles and ethical conduct in research with investigator GCP activities • Identify common sense principles for investigators to implement best practices and GCP in clinical studies

3. Evidence-based Regulatory Science • Reactions to Research Participation Questionnaire for Adults, Children (RRPQ-C) and the RRPQ for Parents (RRPQ-P) • Comparison of time to enrollment for emergency brain-injured subjects in a study with proxy consent versus exception from consent Clinical researchers; • can address human subjects research compliance issues in conjunction with answering their main research questions • should conduct studies that address regulatory compliance issues • can demonstrate investigator proposed research compliance procedures are not based on whim or disregard for subject rights and welfare. Kassam-Adams & Newman, 2002-2006 Wright et al, 2008 Maio, 2008, Excerpts Letter to the Editor, Annals of Emergency Medicine

4. FDA Sponsor-Investigator • FDA Sponsor defined: • “…a person who takes responsibility for and initiates a clinical investigation (21 CFR 312.3(b)” of a drug, device or biologic. • A sponsor may be an individual, a company, an academic institution, a governmental agency or another organization. (Not the same as a financial sponsor) • FDA Sponsor-Investigator: • A sponsor-investigator both initiates and conducts the clinical investigation

5. What are FDA Sponsor Responsibilities? • Determine if a study needs an IND/IDE or is exempt (biologics, off-label use & neutraceuticals most difficult) • Submit an IND or IDE application to the FDA • Follow the IND/IDE application approval process and administrative actions • Meet ongoing IND/IDE sponsor responsibilities during study conduct

6. FDA Sponsor Responsibilities during Study Conduct • Assure the investigator conducts the study according to the protocol and meets investigator responsibilities • Maintain an effective IND/IDE with FDA • FDA submissions-amendment updates, adverse events, annual reports, any other FDA communications • Ensure proper monitoring of study data integrity and subject safety • Assure test-article control and accountability • Provide for records of disposal of the test-article and control of the test article. • Ensure the test article is administered to subjects under the investigator or sub-investigator’s personal supervision and by investigators or staff authorized to administer it • Keep adequate and accurate sponsor records (Maintenance of sponsor master files/binders)

7. FDA Monitoring and Ensuring Quality for SI Studies • FDA recommends sponsors build in quality monitoring so problems can be detected and corrected as close to real time as possible • Focus on key parameters of risk to trial integrity and data quality and to subject safety and protection which allows sponsors to set priorities for using resources appropriately

8. Ethical Principles & GCP • Ethical principles • Inform decision-making • Basis for federal regulations and guidance • Past abuses of ethical principles stimulated development of GCP • Nuremburg • Tuskegee syphilis study • Willowbrook retarded children hepatitis study • Are these ethical lapses and abuses all in the past? • Nicole Wan (healthy volunteer- died), 1996 • Jesse Gelsinger (ineligible-died), 1999 • Ellen Roche (healthy volunteer-died), 2001 • Inadequate monitoring with overdose of pediatric subjects-FDA warning letter to Pfizer, April 9, 2010

9. Ethical PrinciplesBelmont Report-1979 • Respect for persons • Acknowledge autonomy of the individual • Protect those with diminished autonomy • Beneficence • Do no harm • Maximize possible benefits • Minimize possible harms • Justice • Fairness in distribution of burdens and benefits of research participation

10. Regulations • Regulations developed in response to egregious, harmful research conduct • Developed on ethical principles • Regulations are not specific • Regulations don’t address everything that is important in the protection of human subjects • No regulations address decision-making capacity of participants • Regulations MUST be met or sanctions

11. “GCP” Definition • A series of key activities that assures ethical principles, regulations, laws, university policies & procedures are met • NIH-”Scientific and ethical standards of human subject research” • FDA-”Standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials” Data and reported results are credible, and accurate Protects rights, welfare and confidentiality of subjects = Quality Data = Ethics

12. Why GCP? • Failures • Ethical Atrocities • Preventable Research Deaths/Injury • Scientific Fraud • Subject safety • Public trust and support of research mission • Assure valid data for evidence-based Health Care • Drug development trajectory long, arduous, expensive (GCP assures safety and quality data) • Useful products brought to market with known safety profile and effectiveness

13. Informed Consent Obtain Informed Consent

14. Informed Consent as a Process • Interpersonal communication skills assess subject understanding and motivation to participate • Informed consent is freely given and is obtained from each subject prior to study participation • The consent discussion is in language understandable to the participant or the representative and is done by a qualified person • The consent process provides sufficient opportunity for the participant or the participant’s legally authorized representative to consider whether to participate • The consent process minimizes the possibility of coercion or undue influence (Research is not the same as therapeutic txmt) • The consent discussion is free of exculpatory language • The IRB approved document without any changes and with the elements of informed consent is used • Children’s “assent” & “Parental Permission” Adapted from AAHRPP, 2009

15. Informed Consent Review • Privacy respected • Voluntary • Conducted as a process by PI • Process follows the IRB approved protocol • Waiver of consent possible • Consent signed prior to any study procedures • Copy of consent given to subject • Re-consent completed and documented as appropriate • 100% of consents used correct IRB approved version and were appropriately signed and dated

16. What does the public think? CISCRP/ODC Survey, 12/2006

17. Subject Safety Provide for Subject Safety and Clinical Care

18. Adverse Events & Harms . • What is an Adverse event (AE)? • Prevent, monitor for, identify, provide immediate care for, track, analyze cause, provide follow up treatment, report to IRB, may submit protocol amendment or changes to consent document & notify Sponsor (FDA) • IRBMED Guidance and timetable for reporting AEs at http://med.umich.edu/irbmed/ae_orio/ae_report.htm • Harms • Physical • Psychosocial • Social • Economic • Legal • Dignitary

19. What Can Result in Harms? • The protocol/treatment • Side effects of drugs/biologics or adverse device effects • NOT following the protocol • NOT maintaining up-to-date records • NOT maintaining communication with investigator and/or study sponsor • Prevent harm • Qualified person monitors overall study • Monitor laboratory results and tests and treat as appropriate • May withdraw subject from study • Know emergency procedures for breaking a study blind • Keep primary care provider in communication as appropriate • AEs are graded by • Seriousness • Relatedness to the study • Expected/Unexpected

20. The Protocol Follow the Protocol or Amend it

21. A Tension in Research • “The principal duty of a physician is to the well-being of the individual.” • “The principal duty of society (social ethics) is to the greatest good for the greatest number of people.” • Research is protocol driven • Clinicians often want to adapt the protocol for an individual

22. Know and Follow the Protocol • Changes to the protocol, “…may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject.” • Read it • FDA-each person on study team signs it • Protocol Readily Available • No mix ups-Clearly label current version • Follow it • Prevent and track any protocol deviations • Notes to file-circumstances, CAPA • Report to IRB and sponsor as applicable • Amend protocol with IRB as needed • Follow randomization procedures • If applicable, procedures follow data safety and monitoring plan (DSMP) submitted to IRB and funding agencies

23. Confidentiality Maintain Confidentiality

24. Data Confidentiality & Security: Outcomes • Data maintained according to IRB approved protocol • Access to confidential data is restricted • Safe & secure storage • Don’t share passwords! • UM ITS Safe Computing Polices http://www.safecomputing.umich.edu/faculty&staff.php • Mobile device security for researchers at http://www.safecomputing.umich.edu/MDS • UM Electronic data security Questions to Guide Research Protections at OHRCR website http://www.ohrcr.umich.edu/news/electronicdata.pdf

25. Record Keeping & Reports Maintain Accurate, Current, Organized Records and Submit Reports

26. Study Files • Organized, accurate, up-to-date • Direct/Indirect subject identifiers • Direct-subject identifiers stored with data • Indirect-subject identifiers in key & not stored with data • Informed consent-stored with files? • FDA-Complete, sign and submit FDA Form 1572 • Work efficiently • Study schema of subject progress for complex procedures • Checklist of forms completed • Maintain records for: • FDA- two years after FDA approves NDA • NIH- three years after study terminated • HIPAA- six years after study terminated

27. Source Data and Documents (FDA) • All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification • “ALCOA” - Attributable, Legible, Contemporaneous, Original, and Accurate (USE “memo to file”; NEVER use white out or back date) • Source Document Definition • Original documents, data, and records, (e.g., ALL study records such as visits, CRF/Data Collection Forms, and, • Subjective self-report instruments, hospital, clinical and office charts, laboratory notes, notes to file, subject diaries, checklists, pharmacy dispensing records, recorded data from automated instruments, X-Rays, digital records… • Source Data • Generate and Keep source documents in original records • May be using Electronic Data Capture (EDC)

28. The IRB Maintain Communication with the IRB

29. IRB Communications and Submissions • Interact with IRB • Ask questions • Get to know UM IRB contacts • Initial IRB submission and approval • Ongoing oversight • AEs, protocol deviations, unanticipated problems, DSMC reports or safety officer reports, UM OHRCR report, new information that changes risk/benefit of study participation • Continuing review • Terminate a study • Don’t let it expire!

30. Study Oversight & Qualifications

31. Overall PI/Investigator Responsibilities • Ensure a study is conducted according to the protocol or study plan and applicable regulations • FDA Form 1572 • Protect the rights, safety, and welfare of subjects under the investigator’s care • FDA-Control drugs, biological products, and devices under investigation FDA Guidance for Industry: Investigator Responsibilities, Oct 2009

32. Study Oversight by the PI/Investigator • Are individuals who are delegated study tasks qualified to perform them? • Have individuals received training to the protocol and to the tasks? • Is the oversight and involvement in ongoing conduct of the study appropriate? • Where reasonably possible, is there oversight of 3rd parties? Guidance for Industry: Investigator Responsibilities, Oct. 2009

33. Delegating Tasks • The investigator should ensure that any individual to whom a task is delegated is qualified by education, training, and experience (and state licensure where relevant) to perform the delegated task • The level of supervision should be appropriate to the staff, the nature of the trial, and the subject population.

34. Study Logs & Oversight • Delegation log with study roles, tasks and dates worked on study • Signature log with initials log • Train to protocol • Training log • Stay up-to-date on subject and overall study progress • Regular staff meetings (FDA-take minutes)

35. Adequate Resources • Appropriate facilities • Appropriate equipment • Correct equipment available • Calibrated • Preventive maintenance • Study staff training • Proper laboratory facilities (FDA=CLIA certified) • Reference ranges for laboratory tests • Details of analytical methods • Quality assurance information

36. Investigational Product (FDA) Accountability for the Investigational Product

37. Investigational Product • Process investigational product • Receipt (shipping) and Dispensing • Labeling • Accountability to reconcile records for each tablet, compounded drug • Secure storage of device & device return • Return/Destroy drug as determined by sponsor • Interface with Investigational Drug Services / Biomedical Engineering staff, as needed • Investigational products should be manufactured, handled, and stored in accordance with applicable good current manufacturing practice (cGMP)

38. Essential Documents(FDA) Maintain Study Binder

39. Binder Index • ALL important study documentation and correspondence from the study sponsor & study monitor • Delegation, signature log & monitoring log • Signed protocol • Laboratory Information w nl. Values • Equipment information • Blank case report forms (CRFs) • CVs

40. Additional Best Practices • UMHS HIPAA Training • Conflict of Interest Disclosure • Applies to all members of the study team • Includes spouses and dependents • May have a management plan • FDA forms for financial disclosure from sponsor • Maintain all communication with sponsor (FDA) • Shipping specimens • UM personnel who ship infectious substances including patient (clinical) specimens, human-derived research materials, infectious micro-organisms, certain genetically-modified organisms, etc. must complete a training program prior to shipping infectious or biological substances.

41. Summary of “GCP-Best Practices” Key Activities • Obtain Informed consent • Provide for Subject Safety & Medical Care • Follow the IRB approved protocol or submit amendment to IRB • Maintain Confidentiality • Record keeping-Maintain accurate, current, organized records and submit reports • Maintain communication with IRB • Provide appropriate oversight of qualified staff • FDA-Investigational Product Accountability • FDA-Essential Documents Binder • Additional areas • Conflict of interest • Communication with sponsor (FDA) • Shipping regulations ICH-GCP has no statements on ethical principles such as risks, benefits, selection, privacy, vulnerable populations

42. Overall • Legal or regulatory is not always adequate • A personal commitment to integrity needs to be coupled with a firm understanding of “GCP” • The public support of research rests on its trust of scientists, scholars and the institutions • Individual actions are important

43. Ultimate Goal:Responsible Research Practices “The University of Michigan is committed to the highest standards of ethical behavior by faculty, staff, and students engaged in the conduct and administration of research and other scholarly activity.” UM Provost Policy Statement on Academic and Research Integrity

44. Questions?

45. University of Michigan Policies and Procedures • Standard Practice Guide • Approved by Regents • Section 303, http://spg.umich.edu/section/303 • Human Research Protection Program (HRPP) Operations Manual • http://www.hrpp.umich.edu/om/ • IRB Guidance & SOPs • See IRB websites

46. Resources • UM IRBMED & HBHS Workshops • Join MICHR research coordinator email network • Clinical Trials Network (Duke U) • Forms, education, etc. at https://www.ctnbestpractices.org • FDA Device Advice & training • http://www.fda.gov/medicaldevices/deviceregulationandguidance/default.htm • Virtual Regulatory Binder • http://www.partners.org/phsqi/vrb/files/index.htm • NIH-Office of Human Subject Research • http://ohsr.od.nih.gov/ • OHRP Guidance documents • http://www.dhhs.gov/ohrp/policy/ • ICH E6 • http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.pdf