Quorum Review Institution Bulletin V3, iss2


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Quorum Review's Institution Bulletin includes Letter from CEO, Cami Gearhart, JD, addressing OHRP's determination letter referring to consent forms and the SUPPORT trail, as well as Quorum's insights on two important topics: The first addresses consent for legally incapacitated adults and subjects physically unable to sign; the second reviews the recent FDA Subpart D changes on implications for placebo-controlled pediatric trials.

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Quorum Review Institution Bulletin V3, iss2

  1. 1. May 8, 2013 | Volume 3, Issue 2Institution BulletinLetter from the CEOA recent controversy in the news raises difficult issues for IRBs. In 2004 and2005, 22 institutions initiated a study (the SUPPORT trial) of the optimumcare of premature infants. A template consent form was developed andsimilar versions approved by 23 IRBs. The study yielded clinicalinformation hailed as critically important.But earlier this year, the Office for Human Research Protection issued a determination letter critical of the study’sinformed consent forms. OHRP concluded that for one arm of the study, the consent forms identified a possiblebenefit without identifying possible risks; for the other arm, OHRP concluded that the consent forms did notidentify either risks or benefits.The OHRP letter has sparked controversy and criticism. Aside from the specifics of the SUPPORT trial, theletter raises the perennial question: how much information is enough? Regulators, researchers and IRBs areconcerned that consent forms are too long and technical. But the OHRP letter reminds us of the importance offully informing patients and their families of the possible risks and benefits of the proposed research.In this increasingly complex world of research, we all struggle to make the right decisions. To help you with yourhuman research protection program, enclosed are two articles regarding vulnerable populations. One articledescribes the use of legally authorized representatives and witnesses in the consenting process. The othersummarizes recent FDA developments regarding pediatric research.Quorum Review is honored to have the privilege of working with you and your research teams. Please let usknow if we can be of further assistance.Sincerely,Cami Gearhart, CEOQuorum Review IRB
  2. 2. April 25, 2013 | Volume 3, Issue 2Q&A with Quorum: Consent for Legally Incapacitated Adults andSubjects Physically Unable to SignOur practice sees many elderly patientsthat occasionally require someone toconsent on behalf of the patients for their regularmedical treatment. How is consenting different forthese patients in a research context?Before a site can obtain a person’s consent forresearch, the investigator must ensure that anindividual has the decisional capacity to consent tothe research. The investigator may make thisassessment by using a capacity assessment tool, suchas the Mini Mental State Examination (MMSE) orother appropriate tests or evaluations. The FDA andDepartment of Health and Human Services (HHS)define a legally authorized representative (LAR) as,“…an individual or judicial or other body authorizedunder applicable law to consent on behalf of aprospective subject to the subject’s participation inthe procedure(s) involved in the research.”1Local law determineswhether a personcan serve as an LARand what powersthis person has. It isthe investigator’sresponsibility toensure compliancewith his or her local laws and to have a system inplace to ensure that only properly qualified LARsconsent to research on behalf of a participant whodoes not have capacity to provide consent forthemselves.121 CFR 50.3; 45 CFR 46.102.An IRB has the authority to restrict the use of LARsin a study if it determines that it would not beappropriate to enroll individuals who cannotconsent for themselves. For trials that do not presenta therapeutic value to subjects, ICH GCP advisesthat individuals who cannot consent for themselvesshould only be enrolled with the consent of a legalrepresentative when the following conditions arefulfilled: The objectives of the trial cannot be met bymeans of a trial in subjects who can giveinformed consent personally The foreseeable risks to the subjects are low The negative impact on the subject’s well-being is minimized and low The trial is not prohibited by law The approval/favorable opinion of theIRB/IEC is expressly sought on the inclusionof such subjects, and the writtenapproval/favorable opinion covers thisaspect2When an LAR is needed and allowed by the IRB,study staff must conduct the consent discussion withthe LAR, and the consent form must be signed bythe LAR to document their consent. While the FDAand HHS regulations and guidance only require acopy of the consent form be given to the LAR, ICHGCP requires a signed copy of the consent be2ICH E6, Good Clinical Practice: Consolidated Guidance, 4.8.14;available at:http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf(accessed 04/10/2013)
  3. 3. April 25, 2013 | Volume 3, Issue 2While the FDA and HHS regulationsand guidance only require a copy of theconsent form be given to the LAR, ICHGCP requires a signed copy of theconsent be provided to the LAR onceconsent has been obtained.”“provided to the LAR once consent has beenobtained.1Assent from adult participants who lack thedecisional capacity to consent to research should beobtained where possible. Individuals who canprovide assent can sign and date the consent as well,though their signature is not the legally validdocumentation of consent.2Dissent should berespected, and individuals should not be enrolledagainst their wishes. Even if an LAR has authorizedan individual’s participation, an investigator has anobligation to discontinue that individual’sparticipation should the individual express fear,discomfort or any disagreement with studyprocedures.Quorum Review takes several steps to evaluate theenrollment of subjects requiring an LAR in research.First, Quorum requests information from thesponsor and the investigator as to whether theywould allow the enrollment of subjects requiring anLAR in the research. Second, during review of theresearch, Quorum’s Board determines whether theenrollment of such subjects is appropriate for theresearch. If the Board allows the enrollment ofsubjects requiring an LAR, Quorum’s approvaldocuments will indicate this determination. Theinvestigator will also be provided with informationsummarizing local laws that address surrogate1Id. 4.8.12.consent for research. In addition, the consent formprovided to the investigator will include anattestation and signature line for the LAR to indicatetheir consent for the subject to enroll in theresearch.Our research site has a patient whounderstands English, but is illiterate andnot able to sign the consent form. If the patientqualifies and agrees to be in a trial, how can theyindicate their consent to be in the trial?If a participant can understand andcomprehend English, but is unable to sign aconsent form, two steps must be taken to capture theperson’s consent on the consent form:First, a participant must “make their mark”where a participant would normally sign inaccordance with state law. An individual makingtheir mark should be able to make the mark forthemselves without an individual assisting them.If the individual is physically unable to sign, themethod with which they indicate consent needsto be documented on the consent form.Second, an impartial witness must witness theconsent process and attest that they havewitnessed the consent process.3This should bedocumented on the consent form with a witnesssignature line. An impartial witness is someonewho is independent of the trial, who cannot beunfairly influenced by people involved with thetrial, and who attends the informed consentprocess if the subject or legal representativecannot read.43FDA Information Sheet, A Guide to Informed Consent, Last updated:08/09/2011, available at:http://www.fda.gov/RegulatoryInformation/Guidances/ucm126431.htm (accessed 04/10/2013).4ICH E6, Good Clinical Practice: Consolidated Guidance, 1.26.
  4. 4. April 25, 2013 | Volume 3, Issue 2FDA Subpart D Changes:Implications for Placebo-Controlled Pediatric TrialsThe Food and DrugAdministration(FDA) published afinal rule onFebruary 26, 2013,amending Subpart Dof its regulations,which apply toclinicalinvestigationsinvolving children.This rule finalizesthe interim rulepublished in 2001 to bring FDA regulations intocompliance with provisions of the Childrens HealthAct of 2000 (the Childrens Health Act). Theeffective date for the rule was March 28, 2013.The rule updated several definitions, making themconsistent with the parallel HHS Subpart Dregulations. The rule comments and changes to theregulations also clarified the application of theemergency research provisions to children. Thoughthe regulatory changes are minimal, there is anupdated interpretation in the rule comments thathas an impact on the IRB evaluation of placebo-controlled studies in children.In research involving children, IRBs must find thatthe research meets one of three categories underSubpart D before it can be approved. A fourth,seldom used category requires referral of the researchto the FDA.1The three categories are summarizedbelow.1. 21 CFR 50.51: Clinical investigations thatpresent no greater than minimal risk tochildren2. 21 CFR 50.52: Clinical investigationsinvolving greater than minimal risk butpresenting the prospect of direct benefit toindividual subjects (either due tointervention procedure or monitoringprocedure likely to contribute to the subject’swell-being)3. 21 CFR 50.53: Clinical investigations inwhich more than minimal risk to children ispresented by an intervention or procedurethat does not hold out the prospect of directbenefit, if the risk is only a minor increaseover minimal risk, the intervention andprocedures present experiencescommensurate with those in their expectedmedical, dental, psychological, social, oreducational situations; and the interventionor procedure is likely to provide generalizableknowledge about the subject’s disorder orconditionIn the comments to this final rule FDA concludes,the placebo arm of a study does not meet therequirements under §50.52. This section allowsresearch that poses risks that are more than minimal1Clinical investigations not otherwise appropriate that present anopportunity to understand, prevent, or alleviate a serious problemaffecting the health or welfare of children, defined at 21 CFR 50.54
  5. 5. April 25, 2013 | Volume 3, Issue 2if the research offers the possibility of direct benefitto subjects.1 The FDA further explains that armsreceiving investigational products, however, could beconsidered to have direct benefit. Describing theSubpart D analysis this way suggests IRBs shouldconduct a separate analysis of each arm of placebo-controlled studies, as opposed to a single evaluationof the possible benefits and risk for the entire trial.As the FDA notes, it has been recommended byvarious groups, and this approach may be taken bysome IRBs prior to the rule change. However, thecomments indicate this approach would be FDA’sexpectation going forward.Required Parent PermissionIn addition to the IRB analysis of the approvabilityof the research, this interpretation has implicationsfor the IRB determination related to parentpermission. When research poses only a minimalrisk (§50.51) or offers possibility of benefit (§50.52),the IRB can decide whether one or both parentsshould provide permission.2 If the research does notoffer a direct benefit and presents risks that are morethan minimal, Subpart D (§50.53) requires bothparents to provide permission (with some exceptionsif the second parent is unavailable).3Under the FDA’s updated interpretation, IRBs aremore likely to consider a study with a placebo-onlyarm to meet the requirements under §50.53. Thiswill require permission of both parents and two1This is a change from FDA’s previous statement in the interim ruleissued in 2001, which stated: “FDA believes clinical investigationsinvolving placebos in children may be conducted in accord with§50.52. There is evidence of direct benefit to subjects fromparticipating in placebo-controlled trials, including increasedmonitoring and care of subjects, even though a subject may notactually receive the test product. FDA invites comment on the issue ofconducting placebo-controlled trials in children.”221 CFR 50.55(e)(1).signature lines onthe consent forms.When both parentsignatures arerequired, and thesecond parent isnot “reasonablyavailable”—thestandard used inthe regulation—the lack of availability should bedocumented as part of the consent process.321 CFR 50.55(e)(2). Note that the regulations include an exception if“one parent is deceased, unknown, incompetent, or not reasonablyavailable, or when only one parent has legal responsibility for the careand custody of the child if consistent with State law.”Contact Quorum ReviewInterested in learning more about QuorumReview?Our Institutional Team is ready to answer yourinquiries regarding your organization’s specificinstitutional IRB needs.Nancy Jane EarnhardtInstitutional Specialistnearnhardt@quorumreview.comT | 919-930-5198The Institution Bulletin is a special publication of theQuorum Forum, and brought to you by the InstitutionTeam at Quorum Review IRB.