Part 1 of 3 Part Series: Informed Consent: The Document

1. Part 1 of 3 Part Series:Informed Consent: The Document Wendy Lloyd, BA, LPN, CIP, CCRP Regulatory Affairs and Compliance Specialist Process Improvement Team

2. Agenda • Identify consent document requirements • Distinguish between IRB, PI and Coordinators consent document responsibilities • Find the missing pieces in sample consent documents • Identify with what went wrong? Audit results, FDA Warning Letters and OHRP Determination Letters • Summarize tips to avoid deficiencies

3. “Start with the end in mind.” Stephen Covey

4. Why do we have informed consent documents? • Nazi War Crimes • Tuskegee 1932-1972 • Ohio Penitentiary 1955 • Willowbrook Hepatitis Study 1956 • Jewish Chronic Hospital 1963 • Halmsburg Prison 1966 • California Prison System 1967 • Jesse Gelsinger 1999 • San Antonio Contraception study • Ellen Roche 2001 • Victor Trial 2004 • Henrietta Lacks 2010

5. Ethical principals created to protect human subjects: informed consent. • Nuremberg Code – 1947 • 10 points defining points defining legitimate medical research • Declaration of Helsinki – 1964 • Oversight by an IRB • PI sole responsibility is to the subject • HHS Human Subjects Protection Regulations - 1974 • 45 CFR part 46 • Belmont Report - 1979 • Three fundamental ethical principles for all human subjects research: respect for persons, beneficence, and justice • Code of Federal Regulations - 1980 • Regulates clinical investigations of products under its jurisdiction

6. Belmont Report ethical principals: • Respect for Persons • Disclosure of relevant information to prospective subjects about the research • their comprehension of the information, and • their voluntary agreement, free of coercion and undue influence, to research participation • Beneficence • Persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well-being • Justice • Subject selection is fair (burdens and benefits)

7. Who is responsible to ensure consent is correct?

8. Two agencies Regulations regarding consent documents: • DHHS – • 45 CFR Part 46 • FDA 21 CFR • Part 50 (Informed Consent) • Part 56 (IRB)

9. DHHS (45 CFR 46) special protections for vulnerable population. • Fetuses, Pregnant Women, and Human In Vitro Fertilization • Prisoners • Children • Elderly • Cognitively Impaired • Minorities • Etc.

10. 21 CFR 50.20 • No investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative • The information that is given to the subject or the representative shall be in language understandable to the subject or the representative and include the elements of consent

11. 21 CFR 56 • Contains the general standards for the composition, operation, and responsibility of an Institutional Review Board (IRB) that reviews clinical investigations regulated by the FDA

12. Part of IRB responsibility is creating Polices for subject safety: Consent Document must: • Contain the required elements • Complete explanations • Protection of confidentiality • NO unproven claims of effectiveness • Device studies include statement study includes an evaluation of safety of the test article • Consistent with protocol, application, IB and contract • Standard of Care vs. Research • Current IRB template • Contact information

13. Consent Documents Must: • Be IRB approved with a current expiration date • Be legible • Never contain white out • Be filed in the medical/research record (when appropriate), the original copy signed by the participant is retained by the PI • Be written in a language understandable to the subject • Only contain blanks and check boxes that are going to be completed by every subject • Be copied and provided to the subject • Be viewed as an instructional tool rather than a legal tool

14. What is the consent document really? • The informed consent document provides a summary of the research (including the required elements) and explains the subjects rights as a participant • It is designed to outline and be a reference regarding what is expected of the participant • Regulations require a copy be given to the participant.

15. Different types of consent documents. • Standard Consent Document • Adult - 18 and older • Parent/Guardian (Court Appointed) • Children - 12-17 • Assent Document • Child – 7-12 • Script – children under 7 • Short Form – orally presented in conjunction with oral presentation of ICD • Spanish Short Form • Emergency Use • Surrogate Rider for Consent Document

16. Basic elements of the consent document. (21 CFR 50.25) • (1) A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental • (2) A description of any reasonably foreseeable risks or discomfortsto the subject • (3) A description of any benefits to the subject or to others which may reasonably be expected from the research

17. Basic elements of the consent document. • (4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject • (5) A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration may inspect the records • (6) For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occursand, if so, what they consist of, or where further information may be obtained

18. Basic elements of the consent document. • (7) An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject • (8) A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled • (9) A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. Law.  This Web site will not include information that can identify you.  At most, the Web site will include a summary of the results.  You can search this Web site at any time

19. Additional elements of the consent document. • (1) A statement that the particular treatment or procedure may involve risksto the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable • (2) Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent. • (3) Any additional costs to the subject that may result from participation in the research

20. Additional elements of the consent document. • (4) The consequencesof a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject. • (5) A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject. • (6) The approximate number of subjectsinvolved in the study.

21. Is there a time when elements can be omitted? • Waiving Informed Consent: • Research poses no more than minimal risk • Rights and welfare not adversely affected by waiver • Research could not be practicably conducted without waiver • Subjects will be provided with pertinent information after participation, if applicable Remember there is waiver of consent document AND of the consent process.

22. Protecting human subjects is a shared responsibility ME NIH Sponsor Investigator Research Team Compliance Officer Institutional Official Educators Government Auditors Public IRB Chair/Members COG Family Translator Advocates Press /Media FDA DOD Pharmacist YOU OHRP

23. From the mouth of babes -What do subjects want in consent? • Simplicity • Summary • QOL • How many adverse events? • How many visits? • Know how many subjects are on study? • This dose • Different dose

24. Are we doing a good job informing subjects? • 1 out of 7 study volunteers report that they did not read the consent document • Almost 20% opt not to review the ICD with a trusted individual • 70% say they don’teven know what questions to ask • 30 % claim they did not understand that their trial could carry more riskand discomforts than the standard treatment • 1 in 3 did not understand that the investigational drug might be a novel approach to treating their indication • 40 % did not know they had an advocate or ethic representative , other than the PI, to whom they could turn with problems or concerns • 1 out of 5 did not understand that certain authorized individuals would have access to their medical records • 1 in 5 complaints to the FDA is due to ICD noncompliance • Volunteers are most concerned with getting placebo and the risk of side effects Applied Clinical Trials Nov 2002, Informed Consent Process, Kenneth A. Getz

25. What are the Investigators responsibilities? The PRIORITY is to protect the subject Meet the IRB Consent Document requirements PLUS: • FOLLOW the protocol • Become familiar with the Regulations, institutional and IRB Policies • Delegate to appropriately trained individual • Provide supervision and monitor studies • Respond to coordinator, IRB, Sponsor promptly • Encourage KSP attend education sessions • Encourage KSP to become certified • Read the consent document • Revise the document as necessary • Etc.

26. FDA suggestions PI should NOT: • Forget to update consent forms to reflect changes in the Protocol • Over-delegate to non-physicians • Forget to obtain written informed consent and provide oral explanation of the study • Erase, white-out or cover original data entries • Backdate the consent forms and signatures • Forget to obtain IRB approval of consent form revisions • Blame others for inaccuracies • Create fake records • Destroy study records

27. What are the Coordinators Responsibilities? • Comply with the Regulations and Institutional Policies • Communicate with the PI, Sponsor, IRB and other required departments • Fulfill delegated responsibility from the PI only as trained • Create the document using sponsor and IRB template language that subjects can understand • Maintain records in organized fashion for at least 3 years • Document correspondence (FDA, Sponsor, PI and IRB) • Stay current on and seek training • Utilize resources • FDA, OHRP, VHRPP IRB websites • IRB Template language • HRPP staff

28. Everyone knows the rules and follow them, right?

29. What do Auditors/Monitors look for ? • Does the consent document: - include all the necessary elements, - accurately reflect and comply with the protocol, - read legibly and is it understandable, - have IRB date of approval/expiration, - have unique signatures and dates completed, - have option sections been addressed, - is the contact phone number correct? • Is it the correct consent document for the person/population? • Is the correct consent document version used following revisions? • Were ALL blanks completed? • Is the original signed document maintained ?

30. What errors regarding the consent document are found at Sites? • Use of expired or wrong version date of consent documents • Person consenting the subject did not sign the form • All consent documents were not maintained by the PI for the amount of time stated in the protocol • Unable to locate consent documents • Blanks or options in the consent document were not completed • Contact phone number not correct • All required signatures and dates not completed at time of consent or completed with different dates • Consent used for wrong study • Multiple consent documents for same patients with no explanation why

31. FDA Warning Letters • July 19 – IRB failed to ensure ICD contained confidentiality element for one study and contact information for a second study • March 24- IRB approved study allowing consent following study procedures instead of before • January 19 – PI failed to obtain ICD for subjects, During response PI gave ICD to FDA not IRB approved, did not contain all elements AND contained exculpatory language, subject releasing rights • January 28 – PI failed to obtain consent with complete study info (purpose and pregnancy) for 6 subjects, sent 3 saliva spec on subjects who did not complete the optionapproving sampling, conducted lab tests for two subjects without consent

32. OHRP Determination Letters • Nov 10 – IRB approved research involving a waiver of documentation of informed consent without appropriately waiving this requirement • January 28 – IRB approved waiver or alteration of some or all required elements of consent w/o proper documentation • Nov 24 – IRB approved research involving pregnant woman/fetus that held the prospect of direct benefit to the fetus. Only one signature line was on the consent instead of the required two. IRB also approved telephone and electronic consents for studies however did not properly waive documentation or alteration of consent.

33. Helpful hints for Consent document compliance. • Utilize checklist for elements • Use but modify Sponsor consent template • Utilize the template and template language of your IRB • Write out acronyms at first usage • Explain procedures in lay terms • Read the consent and make sure it makes sense • Verify the contact information • Translate, if applicable

34. Checklist of Elements of Consent document Basic elements of informed consent. In seeking informed consent, the following information shall be provided to each subject: • □ (1)A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental, • □ (2) A description of any reasonably foreseeable risks or discomforts to the subject, • □ (3) A description of any benefits to the subject or to others which may reasonably be expected from the research, • □ (4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject, • □ (5) A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration may inspect the records, • □ (6) For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further • Etc.

35. How can the department avoid these errors? • Obtain Sponsor approval for consents and changes prior to submitting to the IRB • Stay organized, file signed consent documents together • Maintain a trail of documentation in your regulatory binder • Double check all blanks and check boxes are completed • Conduct random audits of the consent documents • Attend educational sessions • Review the FDA Warning Letters and FDA IRB Information Sheets –“A Guide to Informed Consent” • Become familiar with the Regulations, state law, institutional and IRB Policies

36. What happens when research is conducted without fully informed consent? The trust based physician-patient relationship may be damaged Non compliance Longer drug approval times Word of mouth about experience Complaints to the IRB, the institution, the OHRP and/or the FDA Subjects no longer willing to participate in research Subjects placed in vulnerable situation Study yield unusable data due to non adherence

37. Conclusion: • It really does start with you • The consent document is the first instructional pieceof information provided to the patient • The common goal of all written consent documents should be complete and clearly written to promote informed decision-making by subjects participating in its research activities • I challenge each of you to make SURE that your participants are fully informed regarding the study so they can make the correct decision for themselves throughout the study

38. “It is the end that crowns us, not the fight.” Robert Herrick

39. References Vanderbilt Human Research Protection Policy IV.A.2. Procedure for incorporating Elements of Informed Consent http://mcapps01.mc.vanderbilt.edu/IRB/policy&procedures.nsf General requirements for informed consent http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46htm#46.106 http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46htm#46.111 http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46htm#46.116 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.20 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.23 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.24 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.25 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.55 Good Clinical Practice E-6 Guidelines http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073122.pdf FDA Warning Letters http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2011/default.htm OHRP Determination Letters http://www.hhs.gov/ohrp/compliance/letters/index.html Links to the historical events in this presentation http://osp.ua.edu/site/PRCO History.html

40. If you have additional comments or questions feel free to contact me Wendy Lloyd Wendy.lloyd@vanderbilt.edu 615-936-7106