Does the Emergency Exception from InformedConsent Process Protect Research Subjects?

Nicole M. DeIorio, MD, Katie B. McClure, MD

AbstractAlthough subject protection is the cornerstone of medicalethics, when considered in the context of research usingemergency exception from informed consent, its success isdebatable. The participants of a breakout session at the2005 Academic Emergency Medicine Consensus Conferencediscussed the issues surrounding subject protection andadvanced the following recommendations. 1) There are nooutcome measures that define ‘‘protection’’; therefore, it isnot currently known whether or not subjects are protectedunder the current rules. 2) Care must be taken to protectnot only the individual from harm during research butalso to protect society from unregulated research in othercountries and an inability to appropriately advance medicalknowledge. 3) Some surrogate markers/methods of protec-tion whose efficacies are debatable include data safety moni-toring board activity, the community consultation andpublic notification (CC/PN) process, and institutionalreview board approval. 4) Minimal-risk studies should beheld to different standards of protection than those thatinvolve more significant risk to the subject. 5) A handfulof studies have been published regarding community

consultation and notification, and the majority are casestudies. Those that are specifically designed to discover themost successfulmethods are hindered by a lack of formal out-comes measures and tend to have negative results. 6) Follow-up data from the CC/PN process should be disclosed to theFood and Drug Administration and incorporated into studydesigns. 7) Focus groups and/or random-digit dialinghave been suggested as promising methods for fulfilling theCC/PN requirements. 8) Studies need to be funded and per-formed that formally investigate the bestmeans of CC/PN. 9)More funding for this research should be a priority in theemergency medicine and critical care communities. Moredata regarding terminated studies should be made availableto the research community. 10) Quantifiable markers ofsuccess for CC/PN must be validated so that research maydetermine the most successful methods. 11) Data regardingsubjects’ and family members’ experiences with exceptionfrom informed consent studies need to be obtained. Keywords: informed consent; ethics; medical research; emer-gencies; resuscitation; emergency medicine. ACADEMICEMERGENCY MEDICINE 2005; 12:1056–1059.

The protection of research subjects is a sine qua nonof medical ethics. A central concern in the debatesurrounding research using emergency exceptionfrom informed consent is whether we are protectingsubjects who have been unknowingly entered intostudies. Clearly, situations such as the Tuskegeesyphilis experiments or the Nazi medical crimes areegregious examples of participants who were notsafeguarded. However, the issues of subject protectionsurrounding research that uses emergency exceptionfrom informed consent are less clear-cut.

How exactly are we to define ‘‘protection of sub-jects’’? The Belmont Report, the 1979 document thatarticulates the foundations of modern ethical think-ing, describes the three basic principles governing

protection of human subjects: beneficence, justice, andrespect for persons. Beneficence signifies the minimi-zation of harm and maximization of possible benefit.Justice indicates that populations benefiting fromresearch should bear its burdens as well. Respectfor persons represents autonomy of subjects yet alsoimplies that researchers should provide extra protec-tion for those with diminished autonomy.1

Can subjects who cannot voice their consent beprotected if their community speaks for them, as man-dated in the current Final Rule? What do we knowabout whether the current Final Rule protects humansubjects?

This report reflects the proceedings of the breakoutgroup charged with discussing the protection of sub-jects. We addressed the literature and expert opinionregarding what is definitively known about thesequestions, our current best recommendations, andways in which future research can help to reach thenebulous goal of human subjects protection.

DISCUSSION QUESTIONS

1. What is empirically known about whether ornot the current rules provide adequate protectionof subjects in resuscitation research? Because

From the Department of Emergency Medicine, Oregon Health &Science University (NMD, KBM) Portland, OR.Received June 24, 2005; accepted June 30, 2005.This is a proceeding from a breakout session of the 2005 AcademicEmergency Medicine Consensus Conference, ‘‘Ethical Conduct ofResuscitation Research,’’ New York, NY, May 2005.Address for correspondence and reprints: Nicole M. DeIorio, MD,Oregon Health & Science University, 3181 SW Sam Jackson Park Rd,Mail code CDW-EM, Portland, OR 97239. E-mail: deiorion@ohsu.edu.doi:10.1197/j.aem.2005.07.001

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‘‘adequate protection’’ is currently a concept thathas not been formally defined and therefore has notbeen measured or studied, vigorous discussion en-sued. Specific issues commented on were as follows.How do the ethical principles of beneficence, jus-

tice, and respect for persons apply to resuscitationresearch? Are we protecting individuals to the detri-ment of society? In the past, research conducted withdeferred consent has been able to advance medicalknowledge in resuscitation situations, such as discov-ering that a previous ‘‘standard of care,’’ high-doseepinephrine, does not routinely improve survivabilityand is not recommended in cardiac arrest.2 Now,however, some of these types of studies may neverbe able to be conducted, such as those that comparetwo currently acceptable treatments. Therefore, mem-bers of populations at risk for emergency events areactually less protected than before. Many in our ses-sion were of the opinion that the rules actually createan incentive for injustice, in that the current situationencourages research in relatively unregulated envi-ronments in other countries. The current Final Rulemay also be promoting off-label use of treatments cur-rently accepted as standard of care yet not proven byrandomized controlled trials because such use couldnot be studied under the tight constraints of the cur-rent rules. However, the group believed that in resus-citation research, beneficence needs to be weightedmore heavily than justice, given the evidence we dohave that the consent process does not truly protectsubjects because they are unable to fully comprehendthe risks/benefits in an emergency situation.3,4

What can serve as surrogate markers of ‘‘protec-tion’’? Some group members argued that methodssuch as intervention by data safety monitoringboards, as occurred in the Diaspirin Cross-LinkedHemoglobin study,5 should be viewed as an instanceof protection. However, others voiced the oppositeopinion, that the fact that the data safety monitoringboard halted a study was an indication that subjectshad not been protected from ostensibly dangerousresearch in the first place. Discussion then turned towhether institutional review board (IRB) approvalcould be used as a marker. Although the PublicAccess Defibrillation (PAD) study was approved at24 IRBs and is an example of successful negotiationof the process,6 many were concerned that this onlyaddresses one aspect of the question, which is actuallyin three parts: is the Final Rule itself appropriate, isthe interpretation of the Final Rule appropriate, andis the implementation of the Final Rule appropriate?IRB approval as a proxy measure only addressesone of these concerns.Next, the community consultation and public noti-

fication (CC/PN) process as a means of protectionwas discussed. Group members raised concerns thatthere is not enough feedback to the Food and DrugAdministration (FDA) after the CC/PN process and

expressed doubt that community response actuallychanges study design. Many articulated the percep-tion that negative community feedback may just en-courage dropping of that particular site, although thenational study would still go on. Further, somebelieved that only the fact that the IRB has approvedthe CC/PN process for a particular study is whatmatters to the FDA. Some called for the establishmentof a formal feedback loop after the community pro-cess so that the FDA may reevaluate the study.

Can protection be achieved using a gradation ofrequirements depending on the risk involved? Cur-rently there is no distinction in the Final Rule betweenminimal and more-than-minimal risk studies; indi-vidual IRBs currently perform risk assessment andinterpretation. The majority of the group endorseddiffering federal rules for CC/PN depending on therisk of participating in the study.

Consensus Statements.

1. We have no outcome measures that define ‘‘pro-tection’’; therefore, we do not currently knowwhether or not subjects are protected under thecurrent rules.

2. Care must be taken to protect not only theindividual from harm during research but alsoto protect society from unregulated research inother countries and an inability to appropriatelyadvance medical knowledge.

3. Some surrogate markers/methods of protectionwhose efficacies are debatable include data safetymonitoring board activity, the CC/PN process,and IRB approval.

4. Minimal-risk studies should be held to differentstandards of protection than those that involvemore significant risk to the subject.

2. What Is known about the best methods ofCC/PN? The published literature was reviewed,and several reports were discussed.3,7–9 Specifically,the report by McClure et al. noted what waitingroom patients or visitors cited as their preferredmethods of notification and the fact that despite astudy conducted using exception from informed con-sent in the community, only 5% were aware of thisstudy. The study by Richardson et al. found no con-sensus among participants of an exception from in-formed consent study with regard to who shouldspeak for them.10 Discussion then ensued involvingthe following.

What constitutes an acceptable percentage of noti-fication? Here the group was divided. Some believedwe should not be responsible for retention rate, onlyfor ensuring that the message has been offered to theappropriate population. A few also believed thatthe rate of retention was not important so much asthe fact that this component of the Final Rule forces

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investigators to plan research they would not beashamed of announcing. No particular percentagecould be agreed upon.

What seems to be the promising future routes forCC/PN? Some investigators are using focus groups ofcommunity members, the benefit being that there areformal methodologies for conducting these and yetthey still allow for community variability. A majorityagreed that a focus group is the best method forgetting started with the CC/PN process, because itallows the pertinent issues and questions to be iden-tified at the outset. Our group believed a particularquestion that could best be answered by focus groupsis, ‘‘Who would be the best community representa-tive for your group?’’ Random-digit dialing wasthen discussed, although the downsides were noted(namely that many people in study populations maynot have telephones); the group did agree this mightbe a good way to generate focus group participants. Inan end-of-conference survey of all conference partic-ipants, however, only eight of 38 viewed this as aneffective means of CC/PN itself.11

Should the definition of ‘‘community represen-tative’’ for those studies involving minimal risk bereconsidered? For example, the community consulta-tion for a low-risk study could simply involve askingthe opinion of the IRB community member or the IRBitself. The idea of graded requirements depending onstudy risk was strongly endorsed by our group.

Should an independent, national advisory groupbe developed, consisting of resuscitation researchers,physicians, and ethicists? Such a group could assessthe scientific validity of studies requesting emergencyexception from informed consent and provide amedical perspective and then give feedback to thelocal IRBs and the FDA. This would solve one prob-lem IRBs often face; they find it difficult to assesswhether a study can feasibly be done with or withoutconsent or assess the scientific merit of a study. IRBmembers in our group echoed this challenge. Ourbreakout group overwhelmingly endorsed this ideaof a national advisory board, as did the entire precon-ference group (31 of 38 respondents).11 Although thepossibility of forming a national IRB specifically ded-icated to reviewing and approving exception frominformed consent protocols has been proposed,12 ourgroup found this to be a suboptimal solution in thatthey believed this model would be less able to takelocal cultural variability into account.

Consensus Statements.

5. A handful of studies have been published regard-ing CC/PN, and the majority are case studies.Those that are specifically designed to discoverthe most successful methods are hindered by alack of formal outcomes measures and tend tohave negative results.

6. Follow-up data from the CC/PN process shouldbe disclosed to the FDA and incorporated intostudy designs.

7. Focus groups and/or random-digit dialing havebeen suggested as promising methods for fulfill-ing the CC/PN requirements.

8. Studies need to be funded and performed thatformally investigate the best means of CC/PN.

3. What are future directions for research? Somediscussion questions and research questions proposedby the group included the following.

What are quantitative indicators for measuringsuccessful CC/PN? What are the most successfulmethods of CC/PN?

What have been subjects’ and family members’experiences in studies that have already taken placeusing exception from informed consent? Did they feeltheir rights had been protected? Did a significantproportion withdraw consent when notified later thatthey had been enrolled? How do family members feelabout being asked for consent after a participant hasdied? Have any lawsuits taken place as a result ofthese studies? Many of the group expressed frustra-tion that so little data regarding terminated studieshave been made available to the research community.

How well is the Final Rule currently understood?How are researchers being educated? Anecdotally,our group recounted many instances of researchersnot understanding the differences between CC andPN or between exception from consent and waiverof consent, for example. They also cited examples ofconfusion regarding who should be responsible forperforming CC/PN: the researcher or the IRB. Amongpreconference participants, only half (19 of 38)11

endorsed the statement, ‘‘I have read the rules andunderstand them.’’ Finally, given that few peopleremain in the FDA who originally developed therules, do current FDA members understand the rules?

Consensus Statements.

9. More funding for this research should be a prior-ity in the emergency medicine and critical carecommunities. More data regarding terminatedstudies should be made available to the researchcommunity.

10. Quantifiable markers of success for CC/PN mustbe validated so that research may determine themost successful methods.

11. Data regarding subjects’ and family members’experiences with exception from informed con-sent studies need to be obtained.

CONCLUSIONS

We hope this report of the proceedings clarifies theissues surrounding human subjects protection under

1058 DeIorio and McClure d PROTECTION OF RESEARCH SUBJECTS

the Final Rule and will be of interest to policymakersand the FDA. As the Final Rule is revisited, thisfeedback should prove helpful in deciding how therule should be expanded, clarified, or otherwiserevised. Furthermore, these findings stress the impor-tance of continued research on this topic, becausemany questions remain.

Participants in the breakout session included Drew Watters, BrookeLerner, James M. Callahan, Ted Glynn, Robert M. Nelson, Amy A.Ernst, Chris Richards, Kennon Heard, Andrew McRae, Art Sanders,David Doezema, Fred Harchelroad, Michael Sayre, Nicole DeIorio,and Katie B. McClure.

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2. Cummins R, ed. ACLS Provider Manual. Dallas, TX: AmericanHeart Association, 2004.

3. Morris MC, Nadkarni VM, Ward FR, Nelson RM. Exceptionfrom informed consent for pediatric resuscitation research:community consultation for a trial of brain cooling afterin-hospital cardiac arrest. Pediatrics. 2004; 114:776–81.

4. Smithline HA, Mader TJ, Crenshaw BJ. Do patients with acutemedical conditions have the capacity to give informed consentfor emergency medicine research? Acad Emerg Med. 1999; 6:776–80.

5. Santora TA, Cowell V, Trooskin SZ. Working through thepublic disclosure process mandated by use of 21 CFR 50.24(exception to informed consent): guidelines for success.J Trauma-Injury Infect Critical Care. 1998; 45:907–13.

6. Mosesso VN Jr, Brown LH, Greene HL, et al. Conductingresearch using the emergency exception from informedconsent: the Public Access Defibrillation (PAD) Trialexperience. Resuscitation. 2004; 351:29–36.

7. McClure KB, DeIorio NM, Gunnels MD, Ochsner MJ,Biros MH, Schmidt TA. Attitudes of emergency departmentpatients and visitors regarding emergency exception frominformed consent in resuscitation research, communityconsultation, and public notification.[erratum appears in AcadEmerg Med. 2003; 10:690]. Acad Emerg Med. 2003; 10:352–9.

8. Baren JM, Anicetti JP, Ledesma S, Biros MH, Mahabee-GittensM, Lewis RJ. An approach to community consultation priorto initiating an emergency research study incorporating awaiver of informed consent. Acad Emerg Med. 1999; 6:1210–5.

9. Shah AN, Sugarman J. Protecting research subjects underthe waiver of informed consent for emergency research:experiences with efforts to inform the community. Ann EmergMed. 2003; 41:72–8.

10. Richardson LD, Wilets I, Ragin DF, et al. Research withoutconsent: community perspectives from the communityVOICES study. Acad Emerg Med. 2005; 12:1082–90.

11. Mann NC, Schmidt TA, Richardson LD. Confronting theethical conduct of resuscitation research: a consensus opinion.Acad Emerg Med. 2005; 12:1078–81.

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