General Principles for Meeting Regulatory Responsibilities

1. General Principles for Meeting Regulatory Responsibilities Terry VandenBosch, RN, PhD, CIP, CCRP Senior Research Compliance Associate Office of Human Research Compliance Review University of Michigan June 1, 2010

2. Today’s Discussion • Describe Best Research Practices (BRP) and Good Clinical Practices (GCP) • Compare GCP requirements for FDA regulated studies and regulatory requirements for non-FDA regulated studies • Identify common sense principles for implementing best practices and GCP in clinical studies

3. What is “Best Practice” • Experience-based • Evidence-based? • Effective and efficient practices to meet • 1) ethical principles • 2) federal regulations & guidance • 4) state laws & practice acts • 5) university policies and procedures • 6) any applicable study SOPs • Best Practices = Responsible Research Practices

4. 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

5. Ethical Principles & Best Practices • Ethical principles inform decision-making and basis for federal regulations and guidance • Past abuses stimulate use of Best Practices • 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-Pfizer FDA warning letter, April 9, 2010

6. Ethical Principles-Belmont • Belmont Report – 1979 • Summarized ethical principals identified by National Commission for the Protection of Human Subjects • Prompted by the Tuskegee Syphilis Experiment and the Willowbrook hepatitis study • 3 basic ethical principles: • (1) Respect for persons • (2) Beneficence • (3) Justice The Tuskegee Study Group were invited to receive "special treatment", which was actually a diagnostic lumbar puncture Peter Buxtun, PHS venereal disease investigator, the Tuskegee “whistle-blower”

7. Respect for Persons Ethical convictions • Acknowledge autonomy of the individual • Protect those with diminished autonomy Applying the principle • Informed consent • The elements of informed consent • Information, comprehension, voluntary • Vulnerable populations

8. Beneficence Ethical convictions • Do no harm • Maximize possible benefits • Minimize possible harms Applying the principle • Investigator & IRB • Minimize risks • Weigh risks and benefits • When appropriate, a plan to monitor and ensure safety

9. Justice Ethical Convictions • Fairness in distribution of burdens and benefits of research participation Applying the principle • Investigator-subject selection • IRB asks “Is the selection of subjects equitable?”

10. Regulations • Regulations developed in response to egregious, harmful research conduct • Developed on ethical principles • Congressional legislation signed into law by President • Laws interpreted in CFR (Code of Federal Regulations) by responsible federal agency • CFR regulations detail how law is implemented • Noncompliance with CFR may result in criminal prosecution, fines, sanctions or debarment from research

11. Regulations(cont’d) • 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 possible subjects • Regulations MUST be met

12. Federal Guidance and Information Sheets • Published by federal agencies to provide more information or to recommend best practices • Interprets application of regulations • Current thinking • NOT legally binding • FDA “… An alternative approach may be used if such approach satisfies the requirements of the applicable statue, regulations, or both…” • Guidance “should” be met

13. 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

14. What is “GCP” • A type of “Best Practice” term coined by the International Conference on Harmonization (ICH) and used by FDA • Refers to FDA regulations, guidance and notices for Drugs, Devices & Biologics • FDA assures …the safety and efficacy of pharmaceuticals, biologics, and medical devices on the market in the U.S.A. • What entities covered by FDA GCP? • IRB • Investigator • Research Sponsor • NIH- “Scientific and ethical standards of human subject research”

15. ICH E6– International Conference on Harmonization • Multi-national body, USA, EU & Japan, est. 1989 • Meets periodically to resolve different technical requirements for drug registration • Goal: Create guidelines and standards for conducting clinical trials allowing sponsors to generate a single set of data to meet submission requirements of the three regions • Originally based on ethical principles from the Declaration of Helsinki-1964 with revisions • Adopted as guidance for drugs/biologics by FDA in 1997 • Also used by FDA in reference to devices

16. ICH-E6 “GCP” Definition • A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that: • the Data and Reported Results are Credible, and Accurate, and that • the Rights, Integrity, and Confidentiality of Trial Subjects are Protected • Adopted as guidance by FDA in 1997 = Quality Data = Ethics

17. FDA Regulations and ICH Guidelines • Companies that wish to have study data accepted by the regulatory agencies in the US, EU, and/or Japan need to follow the ICH guideline. • Differences between FDA Regulations and ICH GCP Guidelines: • ICH Guideline states general principles is more prescriptive than regulations • e.g., 21 CFR 50 requires signature and date of subject while ICH E6 says one should also have the signature of the investigator.

18. 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 • The better the GCP-the sooner the product is available for patients

19. Best Practices, GCP & Types of Studies • Investigator Initiated • May or may not be FDA regulated • NIH (HHS) supported • 45 CFR 46 • 17 Federal agencies and the “common rule” • Part A of 45 CFR 46 • e.g., Dept. of Energy, Dept. of Education • FDA Regulated • 21 CFR 312 Drugs & Biologics • 21 CFR 812 Devices • 21 CFR 50 Protection of Human Subjects • 21 CFR 56 Institutional Review Boards

20. Research Clinical Trials “Best Practices” and ICH E6 GCP • Both can be viewed as a series of key activities or “practices” • Order of activities may vary and may be simultaneous • Multiple parties participate but PI remains accountable • Study scientific and ethical quality achieved by defining key study “best practices” and assuring oversight to implement them

21. “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

22. Negotiation Communication Time management Record keeping Computer Organization Oversight of other research staff Detail-oriented Knowledge of regulations and their application Intimate knowledge of protocol “People and Paper” Skills

23. Informed Consent Obtain Informed Consent

24. 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

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

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

27. “It is a confusing time to be a subject-or to be thinking about becoming one…” Moreno, 2001

28. Subject Safety Provide for Subject Safety and Clinical Care

29. Adverse Events & Harms . • Adverse event (AE) defined • Prevent, monitor for, identify, provide immediate care for, track, analyze cause, 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

30. 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

31. The Protocol Follow the Protocol or Amend it

32. The 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

33. 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

34. Confidentiality Maintain Confidentiality

35. Data Confidentiality & Security: Outcomes • Data maintained according to IRB approved protocol • Access to confidential data is restricted • Safe & secure storage • Don’t share passwords! • 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

36. Implications for Confidentiality • Being notified only, with no re-consent or opt out process, before their information goes to a national database • 47% completely unacceptable • 20% somewhat unacceptable • No notification or re-consent at all, before their information is sent to a national database • 54% completely unacceptable • 16% somewhat unacceptable • How much do current and potential subjects want to be informed, give consent and maintain confidentiality of their data?

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

38. 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

39. ALCOA (FDA) • FDA Documentation Guidance AAttributable (who, when) L Legible (readable, pen, no white out, single line) C Contemporaneous (up-to-date) O Original (source document) A Accurate (verifiable with source)

40. 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 • 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)

41. The IRB Maintain Communication with the IRB

42. 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!

43. Study Oversight & Qualifications

44. 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

45. 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? • Oversight and involvement in ongoing conduct of the study • Where reasonably possible, oversight of 3rd parties Guidance for Industry: Investigator Responsibilities, Oct. 2009

46. 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

47. 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.

48. 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)

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

50. 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 manufacturing practice (GMP)