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

Wendy Lloyd, BA, LPN, CIP, CCRPRegulatory Affairs and Compliance Specialist Process Improvement Team 1

Agenda

• Identify consent document requirements• Distinguish between IRB, PI and Coordinators

consent document responsibilities• Identify with what went wrong? Audit results,

FDA Warning Letters and OHRP Determination Letters

• Summarize tips to avoid deficiencies

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“Start with the end in mind.” Stephen Covey

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Your whole goal should be to provide all the information needed for an informed decision.

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

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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

jurisdiction5

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)

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Who is responsible to ensure consent is correct?

Principal Investigator

Sponsor

IRB Study Coordinator

Pharmacist

Two agencies Regulations regarding consent documents:• DHHS –

• 45 CFR Part 46

• FDA 21 CFR• Part 50 (Informed Consent)• Part 56 (IRB)

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DHHS (45 CFR 46) special protections for vulnerable population.• Fetuses, Pregnant Women, and Human

In Vitro Fertilization• Prisoners• Children• Elderly • Cognitively Impaired• Minorities• Etc.

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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

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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

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Part of IRB responsibility is creating Polices for subject safety:

• 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• Current IRB template• Contact information

Consent Document must:

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Consent Documents Must:• Be IRB approved with a current expiration date

• Be legible

• Never contain white out

• The original copy signed by the participant should be 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

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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

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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• Etc.

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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 discomforts to the subject

• (3) A description of any benefits to the subject or to others which may reasonably be expected from the research

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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 occurs and, if so, what they consist of, or where further information may be obtained

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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

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Additional elements of the consent document.• (1) A statement that the particular treatment or

procedure may involve risks to 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

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Additional elements of the consent document.• (4) The consequences of 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 subjects involved in the study.

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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 documentAND of the consent process.

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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

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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 23

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’t even know what questions to ask• 30 % claim they did not understand that their trial could carry more risk

and 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 effectsApplied Clinical Trials Nov 2002, Informed Consent Process, Kenneth A. Getz

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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.

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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

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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

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Everyone knows the rules and follow them, right?

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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 ?

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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

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FDA Warning Letters• July 19 – IRB failed to ensure ICD contained

confidentiality element for one study and contact information for a second study

• 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 option approving sampling, conducted lab tests for two subjects without consent

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OHRP Determination Letters• 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.

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• 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

Helpful hints for Consent document compliance.

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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. 34

How can the department avoid 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

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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 and/or the FDA

Subjects no

longer

willing to

participate

in rese

arch

Word of mouth about experience

Subjects placed in

vulnerable situationStudy yield unusable

data due to non

adherence

Longer drug

approval times

Conclusion:• It really does start with you• The consent document is the first instructional

piece of 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

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

38Ask yourself is the subject informed enough by the information you provided?

ReferencesVanderbilt Human Research Protection Policy IV.A.2. Procedure for incorporating Elements of Informed Consenthttp://mcapps01.mc.vanderbilt.edu/IRB/policy&procedures.nsfGeneral requirements for informed consenthttp://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46htm#46.106http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46htm#46.111http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46htm#46.116http://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=50.25http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.55

Good Clinical Practice E-6 Guidelineshttp://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/

ucm073122.pdfFDA Warning Lettershttp://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2011/default.htmOHRP Determination Lettershttp://www.hhs.gov/ohrp/compliance/letters/index.htmlLinks to the historical events in this presentationhttp://osp.ua.edu/site/PRCO History.html

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

Wendy LloydWendy.lloyd@vanderbilt.edu

615-936-7106

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