PART 2 OF 3 PART SERIES: INFORMED CONSENT: THE PROCESS Wendy Lloyd BA, LPN, CIP,CCRP Regulatory Affairs and Compliance Specialist 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 "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. REGULATIONS REGARDING CONSENT DOCUMENTS: DHHS 45 CFR Part 46 FDA 21 CFR Part 50 (Informed Consent) Part 56 (IRB) 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 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. 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 ICDs 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 DHHS (45 CFR 46) SPECIAL PROTECTIONS FOR VULNERABLE POPULATION.

Fetuses, Pregnant Women, and Human In Vitro Fertilization Prisoners Children Elderly Cognitively Impaired Minorities Etc. ARE ALL THE RULES THE SAME? ICH/GCP 4.8 suggests 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 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 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 If researchFDA Consent information sheet 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 HOW DO WE KNOW WHAT RULES TO FOLLOW? DHHS OHRP FDA Other Federal Agencies (NIH, CDC and CMS State Law Institutio IRB Policy n Policy IRB Policy Departme nt Policy Research Team SOPs Study

Protocol/ Contract Depending on funding ICH/GCP 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 VALID INFORMED CONSENT REQUIRES: 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. 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 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 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. 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 are not treated like guinea pigs do not suffer more pain or side effects than with standard of care treatment receive high quality care receive honest accurate information 2002 24% 2005 54%

13% 32% 53% 48% 25% However 83 % believe it is essential and very important all new pharmaceutical products be tested on humans before they are approved for general use STRONGLY AGREED THE PROCESS WAS EXPLAINED TO YOU WHEN YOU AGREED TO BE PART OF THE CLINICAL RESEARCH STUDY. 2,261 US adults over 18 surveyed online April 2005 I understood that participation was voluntary. I understood that I was agreeing to participate in a clinical research study. I fully understood what was required of me (number of visits, how long the study lasted, etc.). I knew I could stop participating in the study at any time.

I felt comfortable asking additional questions regarding the study. I was assured confidentiality of all personal information that I provided, with the exception of those allowed by federal law. I felt secure that my confidentiality was protected throughout the study. I was made aware of the benefits involved in participating in the clinical research study. I was made aware of the risks involved in participating in the clinical research study. I understood that I could choose other treatment options, including no treatment at all. The informed consent document was easy to read and understand. 2004 % 90 2005 % 84 89 83

81 78 79 75 79 75 73 73 71 69 74 68 74 65

66 63 60 61 OVERVIEW OF INFORMED CONSENT PROCESS. 2,261 US adults over 18 surveyed online April 2005 % Said purpose of the study was "clear" after reading the informed consent 85 Agreed their questions were answered by the study team regarding the informed consent process 80

Said the study coordinator conducted the informed consent process. 54 Read the informed consent by themselves 48 NewsID=941 WHAT HAPPENS WHEN RESEARCH IS CONDUCTED WITHOUT FULLY INFORMED CONSENT? Non compliance r ug d r ge Lon val ro app s time Wo

r mo d of u abo th exp ut erie nc e Sub j vuln ects p la era ble ced in situ atio n Complaints to the IRB, the institution, the OHRP or the FDA ield Study y due a t a d e

l unusab rence e h d a n to n o ust r t e h T based ani physic t n e i t a p ip h s

n o i relat e may b ed damag ts r c je ge b Su lon g to te no illin cipa rch w r t i ea pa res in PROTECTING HUMAN SUBJECTS IS A SHARED RESPONSIBILITY ME NIH Research Team Compliance Officer Institutional Official Government

Public Members COG Family Advocates FDA DOD YOU OHRP Sponsor Investigator Educators Auditors IRB Chair and Translator Press / Media Pharmacist 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 physicians 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 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 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 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 WHAT ARE THE RESPONSIBILITI ES OF THE PI/DESIGNEE? INVESTIGATOR RESPONSIBILITIES IN INVOLVING SUBJECTS IN RESEARCH

Ultimate protector of the subjects rights and safety Be personally certain that each subject is adequately informed and freely consents to participate in the investigators research Assure that every reasonable precaution is taken to reduce risk to a minimum for the subject The investigator is responsible for whom he delegates authority to Follow the protocol WHAT IS THE PI/DESIGNEES ROLE IN THE CONSENT PROCESS? Obtain consent before initiating ANY studyspecific 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 WHAT IS THE PI/DESIGNEES 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 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 subjects 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 WAYS TO BEGIN THE CONSENT PROCESS? Know the Introduce protocol 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 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 Signed copy given to patient? ___yes ___no Date / Time Copy in patients chart? ___yes ___no INFORMED CONSENT & RECONSENT

Clinical Research Trial: ________________________________ PRESENTATION CHECKLIST 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) Fu do ll siz cu e nt me ba in ck 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:____________________________________________ Physicians Signature (print name):____________________________________Physician (sign): Date:________________________ CONTINUING THE STUDY AND THE CONSENT PROCESS.

Ask if problems arose since last visit (A/Es) 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) 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 WHAT ARE THE RESPONSIBILITI ES OF THE INSTITUTIONAL REVIEW BOARD? 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 OBSERVE THE CONSENT PROCESS You know you want to: Volunteer to have your consenting process observed Contact Wendy Lloyd by phone (9367106) or by email ([email protected]) in advance or just prior to consenting WHAT DO MONITORS/AUDI TORS LOOK FOR? WHAT DO AUDITORS/MONITORS LOOK FOR ?

If SOPs 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 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 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 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 dont hide it Network Become certified If you dont know ask WHO ELSE KNOWS? RELATED 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 FDA WARNING LETTER 2010 RELATED 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. 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 3 rd 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 followup 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 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 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 REFERENCE PAGE For federal guidance on obtaining informed consent of human research subjects, see the following websites: General requirements for informed consent

fr=50.20 fr=50.23 fr=50.24 fr=50.25 Documentation of informed consent fr=50.27 Research involving pregnant women, fetuses or neonates 45cfr46.htm#46.204 45cfr46.htm#46.205 REFERENCE PAGE Research involving children (also found in 21 CFR 50.50-56) Pediatric research assentdecision matrix

Office for Human Research Protections (OHRP) informed consent tips OHRP informed consent FAQ Vanderbilt IRB Policy (WebTableOfContents)/8AF759048966C29D86257731005ECD1F? OpenDocument If you have additional comments or questions feel free to contact me Wendy Lloyd [email protected] 615-936-7106

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