Presentation on theme: "Kimberly Summers, PharmD Deputy ACOS for Research"— Presentation transcript:
1 The Informed Consent Process: From Rules and Regulations to the Protective Value of Ethics Kimberly Summers, PharmDDeputy ACOS for ResearchSouth Texas Veterans Health Care SystemResearch & Development Service
2 Purpose of Consent Process Research subject will…Understand nature of the researchBe continually informed of purpose, risks, benefits, and alternative therapiesMake a voluntary decision about participation or continuation
3 Significant Historical Events in the Development of Informed Consent Nazi atrocities in World War II drew attention to the lack of international standards on research with human participants and led to the formulation of the Nuremburg Code (1948).The thalidomide disaster led to the adoption of the "Kefauver Amendment" (1962) to the Food, Drug and Cosmetic Act, requiring drug manufacturers to prove to the FDA the safety and effectiveness of their products and physicians to obtain informed consent from potential subjects before administering investigational medications.The Declaration of Helsinki drafted by the world Medical Association in 1964 (most recently updated in 2000) builds on the Nuremberg Code and is the basis for Good Clinical Practices used today.The National Research Act (1974) passed primarily in response to the syphilis study, codified the requirement that human participants in research must be protected and set the stage for the issuance of the Belmont Report.
4 Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects in Research Respect for PersonsIndividuals should be treated as autonomous agentsIndividuals with diminished autonomy are entitled to protectionsBeneficenceDo not harmMaximum possible benefits, and minimize potential harmsJusticeFair distribution of burdens and benefits of research
5 Informed Consent: Application of Respect for Persons Initiated before any forms are signedContinues through the completion of the subject's involvement in the studyThe consent document is only a confirmation of the consent processResponsibility of the Principal InvestigatorEven if obtaining signed informed consent is delegated to another study team member
6 Main Components of Informed Consent Selecting participants – Are only those subjects who meet inclusion criteria enrolled? Does the consent form clearly indicate that participation in the research is voluntary?Information - Does the consent form provide all the information necessary for the individual to make a reasoned decision?Comprehension - Is the consent form crafted in language understandable to the potential participant?
7 Selecting Participants Recruitment of participants needs to be done in a nonbiased and non superior to subordinate settingParticipants should never feel that if they do not participate they will be penalizedParticipants should understand why they are being approached for enrollment in the research protocol
8 ExampleOne requirement of Psychology 101 is participation in a study on learning practices.Does this violate the principle of autonomy?Autonomy means a person must have the right to decide not to be in a study. Participation should not be a class requirement.
9 Recruitment: Boundaries Between Practice and Research The distinction between practice and research is often blurred because many times they occur togetherThe researcher and the participant must be able to distinguish practice from researchThe purpose of clinical research is to gain knowledge, not to treat a conditionTherapeutic MisconceptionMisunderstanding that being in a clinical trial is automatically “good” for you
10 Information to Subjects: Describing the Research Research PurposeResearch ProceduresRisksBenefitsCompensationAlternativesConfidentialityDisclosure of Potential Conflict of InterestResearch-Related InjuryContact InformationWithdrawal
11 Informed Consent Document (ICD) IRB template for the ICD covers information required to describe the research to potential research subjectsOnly the most recent IRB approved and stamped consent form can be used to consent subjectsA signed ICD is required prior to any protocol-specific testing being conductedIf protocol specific testing is done the same day as signed informed consent is obtained, must be clear documentation of the chronological order in the medical record
12 Comprehension: Ensure Readability of the ICD Direct the ICD at an eighth-grade reading levelUse simple, straightforward sentencesUse commonly recognizable terms and measurement amountsAvoid the use of jargon or technical languageExplain terms that may not be easily understood
13 Comprehension: Assessing Participant Understanding Ensure that prospective participants understand the extent of their role in the research protocolRead through the consent document with participantsDiscuss participation prior to their involvement in the research protocolAnswer questions and ask open-ended questions
14 ExampleThe principal investigator outlines the risks and benefits to a participant. The participant wants to know of her other options. The investigator does not know of any other options and states this to the potential participant.Is this the correct response to the participant's request?If there are no clear alternatives to participation, the investigator should simply note nonparticipation as an alternative.
15 ExampleThe principal investigator asks a participant to be in her study. The participant agrees, and the investigator has him sign a piece of paper and tells him she will put it in his file. The investigator also says she will mail him information about the study specifics.Does this violate the principle of autonomy?Potential participants must be given information they will need before they decide whether or not to enter a study.
16 Signatures on the ICDFDA 21CFR 50 – The patient or authorized representative shall sign and date the informed consentOHRP 45 CFR 46 - …signed by the patient or legally authorized representativeICH GCP E …the informed consent should be signed and personally dated by the subject or legally authorized representativeVHA Handbook use of a written consent form approved by the IRB and signed and dated by the subject or the subject's legally-authorized representative
17 Witnessing the Informed Consent Process When do you need a witness?When presenting the ICD verballyUse of a short formIf required by the IRBFor all VA research involving an ICDWho can be the witness?ICH GCP: An impartial witness – a person who is independent of the trial, who cannot be unfairly influenced by people involved in the trial, who attends the informed consent processVHA Handbook : role is to witness the subject’s or the subject’s legally-authorized representative’s signature
18 Documenting the Informed Consent Process A statement that the protocol procedures and the informed consent document were reviewed with the participantReview of the risks and benefits of the studyTime for questions to be asked and answeredAlternative treatment options discussedDescription of the participant’s decisionCopy of ICD provided to participant
19 Enrollment Consent Template: Research Consent / Enrollment Note Must be entered into the subject’s health record (CPRS) after IC has been obtainedTemplate in CPRS flags patients Medical Record in postingsTemplate contains all the required information for documentation of consent processTemplate must be used in order to scan IC documentNote must indicate if the study involves the use of investigational medications
20 Consent Document Revisions Study participants must be informed of any new and important information that might affect their willingness to continue participationIf new information, knowledge, or an adverse event has been discovered, it must be communicated to the subjectsThe Principal Investigator must evaluate the new information to decide if a revised consent document is requiredEvaluate if future participants are affectedEvaluate what information should be given to former or current subjectsMay be a requirement of the IRB
21 Auditing vs Monitoring Audits are in addition to the more detailed monitoring of studies by the research team and sponsorAudits are an independent evaluation by someone who is not directly associated with the research
22 VA Research Compliance Office Conduct audits and reviews to ensure compliance with all VA and other Federal requirements for the conduct of researchConduct annual audits of all active studies to insure that informed consent has been properly obtained and documented for each subject since the previous audit22
23 Components of the VA Compliance Audit of Informed Consent Was ICD used for participant the most current IRB approved and stamped document at time of enrollment?Is a ICD present in the participant’s medical record?Is witness’s signature and date present?Is person’s who obtained consent signature and date present?Was delegation of authority to obtain consent appropriate?Do all dates on the consent match?Is the informed consent process documented in progress note?
24 STVHCS Research Compliance Most Recent Audit Summary Feb – May ,376 ICD reviewedIdentified deficienciesWitness signature missingConsent not scanned into CPRSNo documentation of consent process in CPRSMissing HIPAA authorizationStudy procedures performed prior to subject signing ICDFailure to use most current IRB approved and stamped ICD
25 FDA Inspections and Informed Consent Statistics 2007 – 11% of the clinical investigators/sites inspected were cited for informed consent related issues2007 – 32% of the investigators/sites who received Official Action Indicated letters included informed consent citations
26 VA Inspector General (IG) Report VA enrolls a total number of 361,042 human research subjects in its studiesOf those, an estimated 110,230 have noncompliant informed consent documentationIG investigators estimate that over 107,000 consent forms have missing or incomplete witness signatures
28 Jesse Gelsinger18 year old participant in a gene therapy trial conducted at the University of PennsylvaniaSuffered from ornithine transcarbamylase deficiency (OTC)X-linked genetic disease of the liverAt the time of enrollment was doing well on a restricted diet and medicationsEnrolled in a trial to test the safety of a procedure to inject gene therapy with an adeovirus vectorProcedure was being developed for treatment of infants born with OTCNo direct benefit was expected to current participantsJesse died 4 days after initiation of the procedure due to a massive immune response triggered by the adenovirus vector
29 FDA InvestigationConcluded scientists involved, including the lead investigator and the University broke several basic ethical principals
30 Failure to Recruit Based on Inclusion Criteria Participant enrolled despite elevated ammonia levels that met exclusion criteriaJesse’s liver deficiency was worse than any of the previous seventeen research subjects
31 Failure to Fully Describe the Research: Potential Risks The consent form approved by the NIH notified participants that monkeys had died from similar treatmentsThe final consent form distributed to volunteers enrolled at U Penn omitted any mention of the monkey deathsJesse and his parents were not aware of the monkey deaths associated with similar treatments
32 Failure to Fully Describe the Research: Research Procedures The protocol had a dose ranging componentJesse was the first participant assigned to the largest dose groupJesse was not informed that he may receive a dose larger than that given to any previous subject
33 Failure to Revise Informed Consent Document Previous subjects in this trial had experienced severe elevated liver enzymes and serious adverse reactionsThese adverse effects had not been reported to federal regulatorsThe consent form had not been amended to include these reactionsProtocol procedures continued with increasing dosages despite warning signs
34 Failure to Disclose Potential Conflicts of Interest The lead investigator and the University are reported to have had financial stakes in the researchFinancial conflicts of interest for the investigators and/or the institution were not disclosed in the informed consent process
35 Failure to Assess Participants Understanding Statement by PAUL GELSINGER:“Jesse was doing exceptionally well on his medications, and nothing should have prevented him from living a full and happy life. He believed, after discussions with representatives from Penn, that the worst that could happen in the trial would be that he would have flu-like symptoms for a week. He was excited to help.”
36 Was Jesse able to make an informed decision regarding his participation in this trial?
37 Statement by Paul Gelsinger I still support our need for clinical trials, but with this caution: Informed consent is only possible if all facets of the research endeavor are ethical and in the open. Because of the secretive and conflicting influences on clinical research, the average research subject has little hope of understanding and giving truly informed 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 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 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 enabled us to draw attention to the problems currently inherent in clinical research.