The Informed Consent Process: The Informed Consent Process: From Rules and Regulations to From Rules and Regulations to the Protective Value of Ethicsthe Protective Value of Ethics

Kimberly Summers, PharmDKimberly Summers, PharmDDeputy ACOS for ResearchDeputy ACOS for Research

South Texas Veterans Health Care SystemSouth Texas Veterans Health Care SystemResearch & Development ServiceResearch & Development Service

Purpose of Consent ProcessPurpose of Consent Process

• Research subject will…Research subject will…

– Understand nature of the researchUnderstand nature of the research

– Be continually informed of purpose, risks, Be continually informed of purpose, risks,

benefits, and alternative therapiesbenefits, and alternative therapies

– Make a voluntary decision about participation Make a voluntary decision about participation

or continuation or continuation

Significant Historical Events in the Significant Historical Events in the Development of Informed ConsentDevelopment of Informed Consent

• Nazi atrocities in World War II drew attention to the lack of Nazi atrocities in World War II drew attention to the lack of international standards on research with human participants and international standards on research with human participants and led to the formulation of the led to the formulation of the Nuremburg Code Nuremburg Code (1948). (1948).

• The thalidomide disaster led to the adoption of the "The thalidomide disaster led to the adoption of the "Kefauver Kefauver AmendmentAmendment" (1962) to the Food, Drug and Cosmetic Act, " (1962) to the Food, Drug and Cosmetic Act, requiring drug manufacturers to prove to the FDA the safety and requiring drug manufacturers to prove to the FDA the safety and effectiveness of their products and physicians to obtain informed effectiveness of their products and physicians to obtain informed consent from potential subjects before administering consent from potential subjects before administering investigational medications.investigational medications.

• The The Declaration of HelsinkiDeclaration of Helsinki drafted by the world Medical drafted by the world Medical Association in 1964 (most recently updated in 2000) builds on the Association in 1964 (most recently updated in 2000) builds on the Nuremberg Code and is the basis for Good Clinical Practices used Nuremberg Code and is the basis for Good Clinical Practices used today. today.

• The National Research ActThe National Research Act (1974) passed primarily in response to (1974) passed primarily in response to the syphilis study, codified the requirement that human the syphilis study, codified the requirement that human participants in research must be protected and set the stage for participants in research must be protected and set the stage for the issuance of the Belmont Report.the issuance of the Belmont Report.

Belmont Report: Ethical Principles and Belmont Report: Ethical Principles and Guidelines for the Protection of Human Guidelines for the Protection of Human

Subjects in ResearchSubjects in Research• Respect for PersonsRespect for Persons

– Individuals should be treated as autonomous agentsIndividuals should be treated as autonomous agents– Individuals with diminished autonomy are entitled to Individuals with diminished autonomy are entitled to

protectionsprotections

• BeneficenceBeneficence– Do not harmDo not harm– Maximum possible benefits, and minimize potential Maximum possible benefits, and minimize potential

harmsharms

• JusticeJustice– Fair distribution of burdens and benefits of researchFair distribution of burdens and benefits of research

Informed Consent: Informed Consent: Application of Respect for PersonsApplication of Respect for Persons

• Initiated before any forms are signedInitiated before any forms are signed

• Continues through the completion of the Continues through the completion of the subject's involvement in the studysubject's involvement in the study

• The consent document is only a confirmation The consent document is only a confirmation of the consent processof the consent process

• Responsibility of the Principal InvestigatorResponsibility of the Principal Investigator– Even if obtaining signed informed consent is Even if obtaining signed informed consent is

delegated to another study team memberdelegated to another study team member

Main Components Main Components of Informed Consentof Informed Consent

• Selecting participantsSelecting participants – Are only those – Are only those subjects who meet inclusion criteria enrolled? subjects who meet inclusion criteria enrolled? Does the consent form clearly indicate that Does the consent form clearly indicate that participation in the research is voluntary? participation in the research is voluntary?

• InformationInformation - Does the consent form provide - Does the consent form provide all the information necessary for the all the information necessary for the individual to make a reasoned decision? individual to make a reasoned decision?

• ComprehensionComprehension - Is the consent form crafted - Is the consent form crafted in language understandable to the potential in language understandable to the potential participant?participant?

Selecting Participants

• Recruitment of participants needs to be Recruitment of participants needs to be done in a nonbiased and non superior to done in a nonbiased and non superior to subordinate settingsubordinate setting

• Participants should never feel that if they Participants should never feel that if they do not participate they will be penalizeddo not participate they will be penalized

• Participants should understand why they Participants should understand why they are being approached for enrollment in the are being approached for enrollment in the research protocolresearch protocol

ExampleExample

• One requirement of Psychology 101 is One requirement of Psychology 101 is participation in a study on learning practices. participation in a study on learning practices.

• Does this violate the principle of autonomy?Does this violate the principle of autonomy?

• Autonomy means a person must have the Autonomy means a person must have the right to decide not to be in a study. right to decide not to be in a study. Participation should not be a class Participation should not be a class requirement.requirement.

Recruitment: Boundaries Between Recruitment: Boundaries Between Practice and ResearchPractice and Research

• The distinction between practice and research is The distinction between practice and research is often blurred because many times they occur often blurred because many times they occur togethertogether

• The researcher and the participant must be able The researcher and the participant must be able to distinguish practice from research to distinguish practice from research

• The The purposepurpose of clinical research is to gain of clinical research is to gain knowledge, not to treat a conditionknowledge, not to treat a condition– Therapeutic MisconceptionTherapeutic Misconception– Misunderstanding that being in a clinical trial is Misunderstanding that being in a clinical trial is

automatically “good” for youautomatically “good” for you

Information to Subjects:Information to Subjects:Describing the ResearchDescribing the Research

• Research PurposeResearch Purpose• Research ProceduresResearch Procedures• RisksRisks• BenefitsBenefits• CompensationCompensation• AlternativesAlternatives

• ConfidentialityConfidentiality• Disclosure of Disclosure of

Potential Conflict of Potential Conflict of InterestInterest

• Research-Related Research-Related InjuryInjury

• Contact InformationContact Information• WithdrawalWithdrawal

Informed Consent Document (ICD)Informed Consent Document (ICD)

• IRB template for the ICD covers information IRB template for the ICD covers information required to describe the research to potential required to describe the research to potential research subjectsresearch subjects

• Only the most recent IRB approved and stamped Only the most recent IRB approved and stamped consent form can be used to consent subjectsconsent form can be used to consent subjects

• A signed ICD is required prior to any protocol-A signed ICD is required prior to any protocol-specific testing being conductedspecific testing being conducted– If protocol specific testing is done the same day as If protocol specific testing is done the same day as

signed informed consent is obtained, must be clear signed informed consent is obtained, must be clear documentation of the chronological order in the documentation of the chronological order in the medical recordmedical record

Comprehension: Ensure Comprehension: Ensure Readability of the ICDReadability of the ICD

• Direct the ICD at an eighth-grade reading Direct the ICD at an eighth-grade reading levellevel

• Use simple, straightforward sentences Use simple, straightforward sentences • Use commonly recognizable terms and Use commonly recognizable terms and

measurement amounts measurement amounts • Avoid the use of jargon or technical Avoid the use of jargon or technical

languagelanguage• Explain terms that may not be easily Explain terms that may not be easily

understoodunderstood

Comprehension: Assessing Participant Understanding

• Ensure that prospective participants Ensure that prospective participants understand the extent of their role in the understand the extent of their role in the research protocolresearch protocol

• Read through the consent document with Read through the consent document with participantsparticipants

• Discuss participation prior to their Discuss participation prior to their involvement in the research protocolinvolvement in the research protocol

• Answer questions and ask open-ended Answer questions and ask open-ended questions questions

ExampleExample

• The principal investigator outlines the risks and The principal investigator outlines the risks and benefits to a participant. The participant wants to benefits to a participant. The participant wants to know of her other options. The investigator does not know of her other options. The investigator does not know of any other options and states this to the know of any other options and states this to the potential participant. potential participant.

• Is this the correct response to the participant's Is this the correct response to the participant's request?request?

• If there are no clear alternatives to participation, the If there are no clear alternatives to participation, the investigator should simply note nonparticipation as investigator should simply note nonparticipation as an alternative.an alternative.

ExampleExample

• The principal investigator asks a participant to The principal investigator asks a participant to be in her study. The participant agrees, and the be in her study. The participant agrees, and the investigator has him sign a piece of paper and investigator has him sign a piece of paper and tells him she will put it in his file. The investigator tells him she will put it in his file. The investigator also says she will mail him information about the also says she will mail him information about the study specifics. study specifics.

• Does this violate the principle of autonomy?Does this violate the principle of autonomy?• Potential participants must be given information Potential participants must be given information

they will need before they decide whether or not they will need before they decide whether or not to enter a study.to enter a study.

Signatures on the ICD• FDA 21CFR 50 – The patient or authorized

representative shall sign and date the informed consent• OHRP 45 CFR 46 - …signed by the patient or legally

authorized representative• ICH GCP E6 4.8- …the informed consent should be

signed and personally dated by the subject or legally authorized representative

• VHA Handbook 1200.5- use of a written consent form use of a written consent form approved by the IRB and signed and dated by the approved by the IRB and signed and dated by the subject or the subject's legally-authorized representativesubject or the subject's legally-authorized representative

Witnessing the Informed Consent ProcessWitnessing the Informed Consent Process

• When do you need a witness?When do you need a witness?– When presenting the ICD verballyWhen presenting the ICD verbally– Use of a short formUse of a short form– If required by the IRBIf required by the IRB– For all VA research involving an ICDFor all VA research involving an ICD

• Who can be the witness?Who can be the witness?– ICH GCP: An impartial witness – a person who is ICH GCP: An impartial witness – a person who is

independent of the trial, who cannot be unfairly independent of the trial, who cannot be unfairly influenced by people involved in the trial, who attends influenced by people involved in the trial, who attends the informed consent processthe informed consent process

– VHA Handbook 1200.5: role is to witness the VHA Handbook 1200.5: role is to witness the subject’s or the subject’s legally-authorized subject’s or the subject’s legally-authorized representative’s signaturerepresentative’s signature

Documenting the Informed Consent Process

• A statement that the protocol procedures and the A statement that the protocol procedures and the informed consent document were reviewed with the informed consent document were reviewed with the participantparticipant

• Review of the risks and benefits of the studyReview of the risks and benefits of the study• Time for questions to be asked and answeredTime for questions to be asked and answered• Alternative treatment options discussedAlternative treatment options discussed• Description of the participant’s decisionDescription of the participant’s decision• Copy of ICD provided to participantCopy of ICD provided to participant

Enrollment Consent Template: Research Enrollment Consent Template: Research Consent / Enrollment NoteConsent / Enrollment Note

• Must be entered into the subject’s health record Must be entered into the subject’s health record (CPRS) after IC has been obtained(CPRS) after IC has been obtained

• Template in CPRS flags patients Medical Record Template in CPRS flags patients Medical Record in postingsin postings

• Template contains all the required information for Template contains all the required information for documentation of consent processdocumentation of consent process

• Template must be used in order to scan IC Template must be used in order to scan IC documentdocument

• Note must indicate if the study involves the use of Note must indicate if the study involves the use of investigational medicationsinvestigational medications

Consent Document Revisions• Study participants must be informed of any new and Study participants must be informed of any new and

important information that might affect their willingness to important information that might affect their willingness to continue participationcontinue participation

• If new information, knowledge, or an adverse event has If new information, knowledge, or an adverse event has been discovered, it must be communicated to the subjectsbeen discovered, it must be communicated to the subjects

• The Principal Investigator must evaluate the new The Principal Investigator must evaluate the new information to decide if a revised consent document is information to decide if a revised consent document is requiredrequired– Evaluate if future participants are affectedEvaluate if future participants are affected– Evaluate what information should be given to former or current Evaluate what information should be given to former or current

subjectssubjects– May be a requirement of the IRBMay be a requirement of the IRB

Auditing vs MonitoringAuditing vs Monitoring

• Audits are in addition to the more detailed monitoring of studies by the research team and sponsor

• Audits are an independent evaluation by someone who is not directly associated with the research

• Conduct audits and reviews to ensure compliance with all VA and other Federal requirements for the conduct of research

• Conduct annual audits of all active studies to insure that informed consent has been properly obtained and documented for each subject since the previous audit

VA Research Compliance OfficeVA Research Compliance Office

Components of the VA Compliance Components of the VA Compliance Audit of Informed ConsentAudit of Informed Consent

• Was ICD used for participant the most current Was ICD used for participant the most current IRB IRB approved and stamped approved and stamped document at time of enrollment?document at time of enrollment?

• Is a ICD present in the participant’s medical record?Is a ICD present in the participant’s medical record?• Is witness’s signature and date present?Is witness’s signature and date present?• Is person’s who obtained consent signature and date Is person’s who obtained consent signature and date

present?present?• Was delegation of authority to obtain consent Was delegation of authority to obtain consent

appropriate?appropriate?• Do all dates on the consent match?Do all dates on the consent match?• Is the informed consent process documented in progress Is the informed consent process documented in progress

note?note?

STVHCS Research Compliance STVHCS Research Compliance Most Recent Audit SummaryMost Recent Audit Summary

• Feb – May 2009 1,376 ICD reviewedFeb – May 2009 1,376 ICD reviewed• Identified deficiencies Identified deficiencies

– Witness signature missing Witness signature missing – Consent not scanned into CPRSConsent not scanned into CPRS– No documentation of consent process in CPRSNo documentation of consent process in CPRS– Missing HIPAA authorizationMissing HIPAA authorization– Study procedures performed prior to subject signing Study procedures performed prior to subject signing

ICDICD– Failure to use most current IRB approved and Failure to use most current IRB approved and

stamped ICDstamped ICD

FDA Inspections and Informed FDA Inspections and Informed Consent StatisticsConsent Statistics

• 2007 – 11% of the clinical 2007 – 11% of the clinical investigators/sites inspected were cited for investigators/sites inspected were cited for informed consent related issuesinformed consent related issues

• 2007 – 32% of the investigators/sites who 2007 – 32% of the investigators/sites who received Official Action Indicated letters received Official Action Indicated letters included informed consent citationsincluded informed consent citations

VA Inspector General (IG) Report

• VA enrolls a total number of 361,042 human research subjects in its studies

• Of those, an estimated 110,230 have noncompliant informed consent documentation

• IG investigators estimate that over 107,000 consent forms have missing or incomplete witness signatures

Jesse Gelsinger

• 18 year old participant in a gene therapy trial conducted at the University of Pennsylvania

• Suffered from ornithine transcarbamylase deficiency (OTC)– X-linked genetic disease of the liver– At the time of enrollment was doing well on a restricted diet and

medications• Enrolled in a trial to test the safety of a procedure to

inject gene therapy with an adeovirus vector– Procedure was being developed for treatment of infants born

with OTC– No direct benefit was expected to current participants

• Jesse died 4 days after initiation of the procedure due to a massive immune response triggered by the adenovirus vector

FDA Investigation

• Concluded scientists involved, including the lead investigator and the University broke several basic ethical principals

Failure to Recruit Based on Failure to Recruit Based on Inclusion CriteriaInclusion Criteria

• Participant enrolled despite elevated Participant enrolled despite elevated ammonia levels that met exclusion criteriaammonia levels that met exclusion criteria

• Jesse’s liver deficiency was worse than Jesse’s liver deficiency was worse than any of the previous seventeen research any of the previous seventeen research subjectssubjects

Failure to Fully Describe the Failure to Fully Describe the Research: Potential RisksResearch: Potential Risks

• The consent form approved by the NIH The consent form approved by the NIH notified participants that monkeys had died notified participants that monkeys had died from similar treatmentsfrom similar treatments

• The final consent form distributed to The final consent form distributed to volunteers enrolled at U Penn omitted any volunteers enrolled at U Penn omitted any mention of the monkey deathsmention of the monkey deaths

• Jesse and his parents were not aware of the Jesse and his parents were not aware of the monkey deaths associated with similar monkey deaths associated with similar treatmentstreatments

Failure to Fully Describe the Failure to Fully Describe the Research: Research ProceduresResearch: Research Procedures

• The protocol had a dose ranging The protocol had a dose ranging componentcomponent

• Jesse was the first participant assigned to Jesse was the first participant assigned to the largest dose groupthe largest dose group

• Jesse was not informed that he may Jesse was not informed that he may receive a dose larger than that given to receive a dose larger than that given to any previous subjectany previous subject

Failure to Revise Informed Consent Failure to Revise Informed Consent DocumentDocument

• Previous subjects in this trial had Previous subjects in this trial had experienced severe elevated liver enzymes experienced severe elevated liver enzymes and serious adverse reactionsand serious adverse reactions

• These adverse effects had not been reported These adverse effects had not been reported to federal regulatorsto federal regulators

• The consent form had not been amended to The consent form had not been amended to include these reactionsinclude these reactions

• Protocol procedures continued with Protocol procedures continued with increasing dosages despite warning signsincreasing dosages despite warning signs

Failure to Disclose Potential Failure to Disclose Potential Conflicts of InterestConflicts of Interest

• The lead investigator and the University are reported to have had financial stakes in the research

• Financial conflicts of interest for the investigators and/or the institution were not disclosed in the informed consent process

Failure to Assess Participants Failure to Assess Participants UnderstandingUnderstanding

• Statement by PAUL GELSINGER: Statement by PAUL GELSINGER: ““Jesse was doing exceptionally well on his Jesse was doing exceptionally well on his medications, and nothing should have prevented him medications, and nothing should have prevented him from living a full and happy life. He believed, after from living a full and happy life. He believed, after discussions with representatives from Penn, that the discussions with representatives from Penn, that the worst that could happen in the trial would be that he worst that could happen in the trial would be that he would have flu-like symptoms for a week. He was would have flu-like symptoms for a week. He was excited to help.” excited to help.”

Was Jesse able to make an Was Jesse able to make an informed decision regarding informed decision regarding his participation in this trial?his participation in this trial?

Statement by Paul GelsingerStatement by Paul Gelsinger

I still support our need for clinical trials, but with this caution: I still support our need for clinical trials, but with this caution: Informed consent is only possible if all facets of the research Informed consent is only possible if all facets of the research endeavor are ethical and in the open. Because of the secretive and endeavor are ethical and in the open. Because of the secretive and conflicting influences on clinical research, the average research conflicting influences on clinical research, the average research subject has little hope of understanding and giving truly informed subject has little hope of understanding and giving truly informed consent. All research subjects really want is to be able to trust the consent. All research subjects really want is to be able to trust the system. If we can somehow get that system to apply Jesse's system. If we can somehow get that system to apply Jesse's Intent... not for recognition and not for money, but only to help... Intent... not for recognition and not for money, but only to help... then research will get all it wants and more; they'll get research right then research will get all it wants and more; they'll get research right and have a real prosperity, one they never imagined possible. Until and have a real prosperity, one they never imagined possible. Until that happens I am so very grateful that we had a legal recourse that that happens I am so very grateful that we had a legal recourse that enabled us to draw attention to the problems currently inherent in enabled us to draw attention to the problems currently inherent in clinical research.clinical research.

Questions?Questions?

Kimberly Summers, PharmDKimberly Summers, PharmD

Office: (210) 617-5300 ext 15969Office: (210) 617-5300 ext 15969

Email: kimberlyk.Summers@va.govEmail: kimberlyk.Summers@va.gov