PART 2 OF 3 PART SERIES:

INFORMED CONSENT: THE

PROCESSWendy Lloyd

BA, LPN, CIP,CCRPRegulatory 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 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

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?

FDA MandatesFDA 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

ICH/GCP 4.8 suggests

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

research“FDA Consent information sheet”

MORE DIFFERENCE IN FDA VS ICH-GCPFDA 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 proceduresWritten information provided to subjects Information about subject compensation Investigator's current CV and/or other

documents evidencing qualifications

DHHS

OHRP

IRB Policy

IRB Policy

State Law

Institution Policy

Other Federal

Agencies (NIH, CDC and CMS

FDA

HOW DO WE KNOW WHAT RULES TO FOLLOW?

Department Policy

Research Team SOP’sStudy 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.

http://ohsr.od.nih.gov/info/sheet6.html

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 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.

“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”

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=213www.harrisinteractive.com/news/allnewbydate.asp?NewsID=941

2002 2005are not treated like guinea pigs 24% 54%do not suffer more pain or side effects than with standard of care treatment 13% 53%receive high quality care 32% 48%receive honest accurate information 25%

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 2004 2005

% %I understood that participation was voluntary. 90 84I understood that I was agreeing to participate in a clinical research study. 89 83I fully understood what was required of me (number of visits, how long the study lasted, etc.). 81 78I knew I could stop participating in the study at any time. 79 75I felt comfortable asking additional questions regarding the study. 79 75I was assured confidentiality of all personal information that I provided, with the exception of those allowed by federal law.

73 73

I felt secure that my confidentiality was protected throughout the study. 71 69I was made aware of the benefits involved in participating in the clinical research study. 74 68I was made aware of the risks involved in participating in the clinical research study. 74 65I understood that I could choose other treatment options, including no treatment at all. 66 63The informed consent document was easy to read and understand. 60 61

www.harrisinteractive.com/news/allnewsbydate.asp?NewsID=941

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

www.harrisinteractive.com/news/allnewsbydate.asp?NewsID=941

WHAT HAPPENS WHEN RESEARCH IS CONDUCTED WITHOUT FULLY INFORMED CONSENT?

Non compliance The trust based physician-patient relationship may be damaged

Complaints to the IRB, the institution, the OHRP or the FDA

Subjects

no longer

willing to

participate

in research

Word of mouth about experienceSubjects placed in

vulnerable situationStudy yield unusable data due

to non adherence

Longer drug

approval

times

PROTECTING HUMAN SUBJECTS IS A SHARED RESPONSIBILITY ME NIH Sponsor Investigator Research Team Compliance OfficerInstitutional Official Educators Government Auditors Public IRB Chair and Members COG Family Translator Advocates Press / Media FDA DOD Pharmacist YOU OHRP

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

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 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 minimum for the subject

The investigator is responsible for whom he delegates authority to

Follow the protocol

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

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

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

WAYS TO BEGIN THE CONSENT PROCESS?

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

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

INFORMED CONSENT & RECONSENT PRESENTATION CHECKLISTClinical 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 CostsConsent presented to patient / legal representative / legal guardianTime allowed for patient / legal representative / legal guardian to read consent and ask questions prior tosigning consentPatient / legal representative / legal guardian acknowledged understanding of the clinical trial andindicated questions were answered to their satisfactionPatient / legal representative / legal guardian signed informed consentPatient / legal representative / legal guardian received a copy of each signed research consent formStudy specific procedures were not done prior to consent being signedContact information provided to patient / legal representative / legal guardian for study related concernsPerformance 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:________________________

Full size document in back

CONTINUING THE STUDY AND THE CONSENT PROCESS. 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)

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 (936-7106) or by email (wendy.lloyd@vanderbilt.edu)

in advance or just prior to consenting

WHAT DO MONITORS/AUDI

TORS LOOK FOR?

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

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 don’t hide it Network Become certified If you don’t know ask

WHO ELSE KNOWS?

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

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.

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

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 PAGEFor federal guidance on obtaining informed consent of human researchsubjects, see the following websites:

General requirements for informed consenthttp://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?

fr=50.20http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?

fr=50.23http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?

fr=50.24http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?

fr=50.25Documentation of informed consent

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.27

Research involving pregnant women, fetuses or neonateshttp://www.hhs.gov/ohrp/humansubjects/guidance/

45cfr46.htm#46.204http://www.hhs.gov/ohrp/humansubjects/guidance/

45cfr46.htm#46.205http://www.hhs.gov/ohrp/humansubjects/guidance/

45cfr46.htm#46.206http://www.hhs.gov/ohrp/humansubjects/guidance/

45cfr46.htm#46.207

REFERENCE PAGEResearch involving children (also found in 21 CFR 50.50-56)

http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.404http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.405http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.406http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.407http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.408http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.409

Pediatric research “assent”decision matrixhttp://www.hhs.gov/ohrp/panels/407-01pnl/riskcat.htm

Office for Human Research Protections (OHRP) informed consent tipshttp://www.hhs.gov/ohrp/policy/index.html

OHRP informed consent FAQhttp://answers.hhs.gov/ohrp/categories/1566

Vanderbilt IRB Policyhttp://mcapps01.mc.vanderbilt.edu/IRB/policy&procedures.nsf/

(WebTableOfContents)/8AF759048966C29D86257731005ECD1F?OpenDocument

If you have additional comments or questions feel free to contact me

Wendy LloydWendy.lloyd@vanderbilt.edu

615-936-7106