Part 2 of 3 part series: Informed consent: The Process

1. Part 2 of 3 part series: Informed consent: The Process Wendy Lloyd BA, LPN, CIP,CCRP Regulatory Affairs and Compliance Specialist

2. Objectives • Identify consent process requirements • Distinguish between IRB, PI/Designee consent process responsibilities • Identify with what went wrong? Audit results, FDA Warning Letters and OHRP Determination Letters • Summarize tips to avoid deficiencies

3. "A word is not a crystal, transparent and unchanged; it is the skin of a living thought and may vary greatly in color and content according to the circumstances and the time in which it is used" — Oliver Wendell Holmes Jr.

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

5. 45 CFR 46.116 (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

6. 21 cfr 55.109 (b) • An IRB shall require that information given to subjects as part of informed consent is in accordance with 50.25. • The IRB may require that information, in addition to that specifically mentioned in 50.25, be given to the subjects when in the IRB's judgment the information would meaningfully add to the protection of the rights and welfare of subjects.

7. IRB Policy: Procedure for Obtaining Legally Effective and Prospective Informed Consent • Detailed description of the method for obtaining informed consent • All informed consent documents submitted for IRB approval • Changes in ICD’s are submitted as amendments • Consent must contain all required elements • Consent is documented in writing through the use of a current IRB-approved ICD, unless waived • PI assures the informed consent process in research is an ongoing exchange of information throughout the course of the research and it is documented

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

9. ICH/GCP 4.8 suggests Are all the rules the same? • ICH allows the delegation of the informed consent process to a designee • ICH recommends the person conducting the informed consent process sign and date the consent form • ICH recommends that the subject receive a signed and dated copy of the consent form FDA Mandates FDA has no regulations concerning delegation of consenting although it is discussed in the FDA Information Sheets FDA only requires that a copy of consent be provided to subject If consent is obtained the same day that the subject's involvement in the study begins, the subject's medical records/case report form should document that consent was obtained prior to participation in the research“FDA Consent information sheet”

10. More difference in FDA vs ICH-GCP FDA and ICH BOTH require the IRB to review • The informed consent, • process, • protocol, • advertisements, and • the Investigator's Brochure ICH/GCP 3.1 also recommends IRB submission of: • Subject recruitment procedures • Written information provided to subjects • Information about subject compensation • Investigator's current CV and/or other documents evidencing qualifications

11. How do we know what rules to follow? • DHHS • OHRP • FDA • Other Federal Agencies (NIH, CDC and CMS • State Law • Institution Policy • IRB Policy • Department Policy • IRB Policy Research Team SOP’s ICH/GCP • Study Protocol/ Contract Depending on funding

12. What is the consent document? • A document that provides a summary of the research and explains the subjects rights as a participant • It is designed to outline and be a reference regarding what is expected of the participant

13. Valid informed consent requires: • Disclosureof 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. http://ohsr.od.nih.gov/info/sheet6.html

14. 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

15. Barriers to understanding informed consent. • Cognition/capacity • Level of education • Social/cultural values • Language • Age • Environment • Anxiety/fear • Pain • Influence of medications • Quality of disclosed information • Readability of informed consent

16. therapeutic misconception: “the belief that the purpose of a clinical trial is to benefit the individual patient rather than to gather data for the purpose of contributing to scientific knowledge” • The subject believes that his medical needs will determine his assignment to a treatment group or the PI will modify the protocol to serve his own medical need. • The subject has unreasonable expectations about the likelihood of benefit from study participation. In this example the subject believes the PI will not administer treatment that might harm them, but rather, will provide interventions that only help them.

17. Factors that contribute to the lack of subject participation in clinical trials. • Harris Interactive Online Studies of 2031 and 2261 adults • Only a minority of the public is confident that clinical trials subjects However • 83 % believe it is essential and very important all new pharmaceutical products be tested on humans before they are approved for general use www.harrisinteractive.com/news/allnewbydate.asp?NewsID=213 www.harrisinteractive.com/news/allnewbydate.asp?NewsID=941

18. Strongly agreed the process was explained to you when you agreed to be part of the clinical research study. www.harrisinteractive.com/news/allnewsbydate.asp?NewsID=941

19. Overview of informed consent process. www.harrisinteractive.com/news/allnewsbydate.asp?NewsID=941

20. 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 or the FDA Subjects no longer willing to participate in research Subjects placed in vulnerable situation Study yield unusable data due to non adherence

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

22. Who Can consent subjects? The person must be trained regarding informed consent process and be knowledgeable about study • FDA Requirements: • IRB must know who will conduct consent process • FDA does not require the that the PI personally conduct the consent process. • ECOG Requirements: • “Legally, it is the physician’s responsibility to discuss the study with the patient and obtain the written consent.” • “After an initial discussion it may be the physician, nurse, or CRA who provides further details to the patient.” 7.2.6 “Presenting the Consent Form to the Patient,” ECOG Protocol Management

23. The Consent Process is: • Ongoing • Interactive process • Different for every subject • Different for every study • Essential for study success • IRB approved • Providing clear definition between where standard of care leaves off and research begins • Allows re-education • Requires re assessment of subject understanding with each visit

24. Is there a time when the process can be Waived or altered? • Emergency, life threatening situation that requires intervention • Minimal risk study with IRB approval

25. We are all responsible. • Although the regulations place the burden of responsibility on the PI, the protection of human research subjects is a shared responsibility among all research professionals involved in the conduct of the study • Members of a research team have a moral obligation to uphold the ethical and regulatory standards by which human subjects research is conducted I challenge you not to accrue, accrue, accrue but to inform, inform, inform

26. What are the Responsibilities of the PI/Designee?

27. Investigator Responsibilities in involving subjects in research • Ultimate protector of the subject’s rights and safety • Be personally certain that each subject is adequately informed and freely consents to participate in the investigator’s research • Assure that every reasonable precaution is taken to reduce risk to a minimumfor the subject • The investigator is responsible for whom he delegates authority to • Follow the protocol

28. What is the PI/Designee’s Role in the Consent Process? • Obtain consent before initiating ANY study-specific procedures • Provide a quiet, comfortable, and private setting • Explain the consent procedures and process to the subject • Ensure sufficient time to consider all options • Access the subject's reading abilities, cognitive status now and throughout study • Requires accessing subjects understanding

29. What is the PI/Designee’s Role in the Consent Process? • Ensure the subject is the one who wants to participate, free from coercion or other undue influence • Consistent with IRB approved process • Provide additional safeguards as required • Provide new information promptly • Provide a copy of the consent document and each revised consent document to the subject • Document process and response from patient

30. Ways to facilitate the two way conversation and enhance understanding. • Establish a relationship with the subject • Provide privacy • Assess views on research vs. standard of care • Keep the subject in the center of the process • Be an active listener • Ask open-ended questions • Be aware of non-verbal messages • Empathize with the subject’s concerns • Be a teacher by educating the subject and verifying his understanding of the research study • Assure withdrawal is possible at ANY time • Inform other options are available • Be available anytime for any question • Do not rush the process or the subject

31. Know the protocol Introduce yourself and state who referred you Do not depend on subject enrolling You are not a salesman Provided consent document for review Methods of conveying information differs Check list Read consent to subject Read highlights /review calendar Video Electronic Web-based resources Ways to begin the consent process?

32. Informed Consent Worksheet • Date of Consent:__________________ Name of Study:_____________________________ • IRB Study Number:__________________________ • Patient Name:_____________________ Patient MRN:_________________ _Study ID#:__________ • The following has been explained to the potential study subject, and the subject has been offered the opportunity to ask questions regarding the study: • TOPIC • COMMENTS • Purpose of the study _________________________________ • Qualifications to participate _________________________________ • Location and participants _________________________________ • What will happen during the study _________________________________ • Risk and benefits _________________________________ • Study related injury or illness _________________________________ • Alternative treatments _________________________________ • Confidentiality _________________________________ • Study costs _________________________________ • Compensation _________________________________ • Who to contact with questions _________________________________ • Voluntary participation _________________________________ • Termination of participation _________________________________ • Questions or comments: __________________________________________________________________ • __________________________________________________________________ • Does the patient state an understanding of the study and procedures and agree to participate? ___yes ___no • _____________________________________ __________________________ • Person administering consent Date / Time • Signed copy given to patient? ___yes ___no Copy in patients chart? ___yes ___no

33. Full size document in back INFORMED CONSENT & RECONSENT PRESENTATION CHECKLIST Clinical Research Trial: ________________________________ Version Date:________________ Physician discussed diagnosis and treatment options (standard of care, no treatment) Physician discussed clinical research trial including the following: • Description of the clinical research trial, its goals, and medications involved • Voluntary participation • Anticipated duration of participation • All known risks: reported side effects and management of known side effects and… • Possibility of unknown side effects • Potential and reasonable expected benefits • Treatment groups and randomization (if applicable) • Required study procedures • Follow-up after completion of study treatment • Rights and responsibilities of research participants (including contraception if applicable) • Confidentiality • Compensation / Additional Costs Consent presented to patient / legal representative / legal guardian Time allowed for patient / legal representative / legal guardian to read consent and ask questions prior to signing consent Patient / legal representative / legal guardian acknowledged understanding of the clinical trial and indicated questions were answered to their satisfaction Patient / legal representative / legal guardian signed informed consent Patient / legal representative / legal guardian received a copy of each signed research consent form Study specific procedures were not done prior to consent being signed Contact information provided to patient / legal representative / legal guardian for study related concerns Performance Status today (per protocol): Karnofsky/ __________ Lansky ECOG / Zubrod / WHO ___________ Consent document(s) signed on: / / Amount of time explaining the consent:________________ Time consent signed:_______ AM/PM **Translation Services: Translated document(s) and / or interpreter provided as needed: q NO (translation services not needed) _____ YES List language provided:______________________ Any additional comments regarding translation:____________________________________________ Physician’s Signature (print name):____________________________________Physician (sign): Date:________________________

34. Ask if problems arose since last visit (A/E’s) Provide new information if applicable Encourage questions each visit Talk about what comes next Re-assess subjects desire to continue each visit Assess compliance (diary, meds etc) Continuing the study and the consent process.

35. When to re-consent. • If subject regains cognitive ability • New information becomes available • Significant protocol changes • New surrogate is identified • IRB instructs you to re-consent • Investigator has the option to re-consent for longitudinal data collection time points

36. What are the Responsibilities of the Institutional Review Board?

37. What does the IRB look for regarding the informed consent process? • Method of presentation • Voluntary participation • Environment • Complete explanations • Length of time devoted to the process • Simple explanations • Adequate time offered to ask questions • How subject demonstrates understand of the study and desire to participate • Promptness of reporting new information

38. Observe the consent process You know you want to: • Volunteer to have your consenting process observed • Contact Wendy Lloyd by phone (936-7106) or by email (wendy.lloyd@vanderbilt.edu) in advance or just prior to consenting

39. What do monitors/auditors look for?

40. What do Auditors/Monitors look for ? • If SOP’s exist are they followed? • Confirm consent process documentation • Implementation of changes only after IRB approval • Correct version non expired consent used • All options completed by subject • Consent signed and dated by all parties • Consent signed prior to ANY procedures • Consented by trained individuals

41. problems observed in the informed consent process. • Signatures of subject and consenting person on different dates • Consent and study procedures on same date • Consent was performed by an untrained or unqualified care provider • Person consenting is not listed as KSP • Check boxes within the consent incomplete • Crossed out sections or white out used in the IRB approved consent • Unable to locate consent for subject on study • Subjects not re-consented with revised consent as instructed • Ineligible subjects enrolled • Multiple consent documents for same patient with no explanation why • Person consenting did not state the purpose or procedures of the study • Consent document left on clip board for subjects to complete and return to nurse if interested • Person consenting the subject did not sign the form

42. How can your Department avoid deficiencies? • Confirm all personnel consenting subjects are KSP • Document training and qualifications of all KSP • Establish one place to retrieve ONLY the latest IRB approved consent • Conduct random audits of the consent documentation • 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

43. How can You avoid negative findings? • Know the protocol • Only do what you are trained to do • Volunteer for consent observation • Ask subjects if they felt fully informed • Seek education • Stay organized • If you find something don’t hide it • Network • Become certified • If you don’t know ask

44. Who else knows?

45. FDA Warning Letter 2010related to informed consent • January 19 – PI failed to obtain ICD for subjects (? Number), During response PI gave ICD to FDA not IRB approved • January 28 – PI failed to obtain consent with complete study info, conducted lab tests for two subjects without consent • February 18- PI failed to consent 1 subject (hand writing not subjects), enrolled 4 ineligible subjects • February 24 – PI failed to obtain legally authorized ICD: child was enrolled with 1 parent signature, child was in DHS custody • February 25 – PI failed to obtain legally authorized consent; implemented changes in the investigational plan without approval • March 2 – 7 of 25 subjects met EXCLUSION criteria, failed to properly consent 3 subjects, 1 was told would receive investigational device but received control device

46. FDA Warning Letter 2010related to informed consent • March 18 – PI failed proper monitoring of the investigational study • March 10 – PI failed to notify subjects following study participation regarding safety events • March 21- PI failed to consent 2 subjects, 4 ineligible subjects enrolled • March 24- IRB approved protocol allowing consent following study procedures instead of before • April 1- PI failed to consent 1 subject, response letter found consent but it was visibly altered and the PI did not alter it. • June 28 – PI failed to consent with updated consent for 7 subjects, enrolled 7 subjects who were ineligible.

47. Ohrp determination letters 2010 related to informed consent • January 28 – IRB did not document specific criteria when approving waiver or alteration of consent • January 29 – IRB did not waive consent for subjects, PHI was obtained from family members and the approved consent did not contain the appropriate risk language • April 8 – PI retain PHI on subject for a study without approval or consent. PI also implemented study changes (a 3rd intervention) without IRB approval • June 3 – PI decided not to inform subjects of new drug information since they had completed the study and PI did not conduct all follow-up visits (although subject was in the office) per protocol requirements • 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. • May 10- subject complained he was encouraged to continue a study he did not wish to continue in

48. Personal Best • Each interaction is different because every subjects, circumstance, question, communication style is different. • It is up to each one of us to take the consent process serious and fully inform each subject

49. We will all benefit from a more effective ICD process: • By possibly increasing subject recruitment and retention on a wide scale • Playing a substantial role in shaping public perceptions of the value of clinical research

50. Reference Page For federal guidance on obtaining informed consent of human research subjects, see the following websites: General requirements for informed consent 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 Documentation of informed consent http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.27 Research involving pregnant women, fetuses or neonates http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.204 http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.205 http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.206 http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.207