A primer for clinical researchers in the emergency department: Part I: Ethical and regulatory background

REVIEW ARTICLE

A primer for clinical researchers in theemergency department: Part I: Ethical andregulatory backgroundemm_1320 399..406

Andrew Davidson1 and Franz E Babl21Department of Anesthesia and Pain Mangement and 2Emergency Department, Royal Children’sHospital, Murdoch Children’s Research Institute and University of Melbourne, Melbourne, Victoria,Australia

Abstract

Research is an important part of emergency medicine and provides the scientific under-pinning for optimal patient care. Although increasing numbers of emergency physiciansparticipate in research activities, formal research training is currently neither part ofemergency physician training in Australia nor easily available for clinicians interested inclinical research. In a two-part series, which is targeted at part-time clinical researchers inthe ED, we set out and explain the key elements for conducting high-quality and ethicalresearch. In Part I, we describe important underlying ethical principles for research inhumans and explain key regulatory processes and documents pertaining to good clinicalresearch practice in Australia. The ethics of research in children as a particularly vulner-able group will also be addressed. Part II will address important elements of researchscience and conduct.

Key words: child, emergency department, ethics, research.

Introduction

Research is increasingly providing the evidence basefor clinical practice in emergency medicine. Moreemergency physicians and nurses are involved inresearch and trainees are mandated to conductresearch projects in order to fulfil training require-ments. Yet many clinicians participating in researchwill not have had formal research training. Apartfrom those who undertake higher degrees, formal

research training is not part of Australian Collegeof Emergency Medicine or Royal Australasian Collegeof Physicians advanced training requirements. Inthe UK, the College of Emergency Medicine hasrecognized this lack of training of ED physicians asan impediment to higher research quality and outputand is planning a formal web-based education pro-gramme for good clinical research practice (GCRP)1

(Prof TJ Coats, University Hospitals of Leicester,2009).

Correspondence: Associate Professor Franz E Babl, University of Melbourne, Emergency Department, Royal Children’s Hospital,Parkville, Vic. 3055, Australia. Email: [email protected]

Andrew Davidson, MB BS, MD, FANZCA, Paediatric Anaesthetist, Associate Professor; Franz E Babl, MD, MPH, FRACP, FAAP, FACEP,Paediatric Emergency Physician, Associate Professor.Financial support: Murdoch Children’s Research Institute, Melbourne, Australia.

doi: 10.1111/j.1742-6723.2010.01320.x Emergency Medicine Australasia (2010) 22, 399–406

© 2010 The AuthorsEmergency Medicine Australasia © 2010 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine

At the same time, both national and local regulatoryrequirements have become more complex. Addition-ally, in the current public hospital system the focus ison clinical services, and therefore resources to hireED-based professional research staff are limited.

The research regulatory model in Australia haspredominantly relied on an under resourced HumanResearch and Ethics Committee (HREC) system,2,3

whose focus is research permission rather than moni-toring for ethical problems during the execution of theproject or ensuring that research is conducted to a highstandard. Although the latest national documents havenow more clearly defined the responsibility of the insti-tution in maintenance of quality in research,4,5 much ofthe responsibility for following GCRP still rests with theindividual researcher.

In spite of standards of research that researchersshould, or in some circumstances must follow, manyresearchers might be unaware of these standards orchose to ignore them. In our ED based at a tertiarychildren’s hospital, an internal audit identified anumber of problems of research practice that requiredrectification: suboptimal database protection, incom-plete case report forms, lack of de-identification ofdata forms after study completion, randomized con-trolled trials not registered with a clinical trials regis-try and deficits in data storage practices. There wasno formal mandatory research training for ED staff.A subsequent survey of the research knowledge ofclinical researchers at the affiliated research institute –including our ED – showed a lack of knowledgeand understanding about key research related regula-tory documents and GCRP related topics.6 FormalGCRP training had been undertaken by only 10%of staff and few had experienced a research projectaudit.

Standards of good research can be grouped into threethemes: research must be ethical, research must be con-ducted rigorously and the science should be sound. Thethree are closely linked. This two-part series, which istargeted at part-time clinical researchers and trainees, isdesigned to be a primer of the key topics surroundingthe ethics and mechanics of quality ED research. In PartI, it reviews key ethical concepts, the major Australianregulatory documents pertaining to GCRP, the ethicsapproval process and research misconduct. In Part II, itwill address important topics of research science andadministration. It is not the purpose of this review toprovide an exhaustive list of all rules and regulationsnor can it present an in-depth discussion of all ethicalissues.

Ethical concepts

Brief historical background

During World War II, medical experiments were con-ducted by the Nazis and others in the name of medicalscience. In response to these atrocities a written code ofmedical ethics was developed and resulted in theNuremberg Code.7 A central theme in the code is theneed for fully informed consent. It was later recognizedthat the code had limitations and in 1964 the WorldMedical Association produced a clinical research ethicscode known as the Declaration of Helsinki. Variousmodifications have since been made to the Declaration.8

A key early document developed in the USA was theBelmont Report published by the National Commissionfor the Protection of Subjects of Biomedical and Behav-ioral Research in 1979.9 The commission was estab-lished partly because of public outrage and UScongressional concern after the Tuskegee syphilisexperiments conducted from the 1930s in the USA10 TheBelmont Report did not produce a guideline or rules butprovided a framework of principles on which to basedecisions about the ethics of medical research. The threeunderlying principles were respect for the individual,beneficence and justice. These three principles stillunderpin most ethics guidelines. In 1993, the Council forInternational Organizations of Medical Sciences and theWorld Health Organization also published the Interna-tional Ethical Guidelines for Biomedical ResearchInvolving Human Subjects.11 In Australia, the NationalStatement on Ethical Conduct in Human Research4

(often shortened to ‘National Statement’) by the NationalHealth and Medical Research Council (NHMRC) is theoverarching guideline for ethical research and incorpo-rates the three principles of the Belmont report with theadditional principle of ‘research merit and integrity’.12

Key principles and concepts

Respect for personsRespect for persons recognizes the value of autonomy toan individual. Wherever possible, participants inresearch must have the power to make their own deci-sions. Having respect for persons also requires havingdue regard for the beliefs, customs and cultural heritageof individuals, and respecting privacy and confidential-ity. Consent is the key element of respect for persons.The consent to participate in a research project must befree and informed. Free consent implies a voluntary

A Davidson and FE Babl

400 © 2010 The AuthorsEmergency Medicine Australasia © 2010 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine

choice not influenced by external coercion, pressure orinducement. Informed consent implies the participanthas sufficient information and adequate understandingof the proposed research and the implications of partici-pation. Coercion and inducement may be subtle. Forexample, if the researcher is also the clinician lookingafter the patient, then the patient may be reluctant torefuse involvement in research fearing any implicationthis would have on the doctor–patient relationship.Another example is the use of financial inducements.The National Statement generally does not allow finan-cial rewards to induce participants to take risk.

BeneficenceThe principle of beneficence includes the concept ofmaximizing possible benefits and minimizing possibleharms and avoiding unnecessary burdens. The prin-ciple of beneficence can also be extended to include thelikely impact of the research on the community as awhole. Non-maleficence is often included as anotherprinciple related to beneficence. Non-maleficence con-cerns doing no harm, or at the least only doing actswhere the intention is that the harm to be suffered by anindividual will be greatly exceeded by the benefitaccrued by that same individual.

Non-therapeutic research, that is, research where therisk of harm is possibly greater than the risk of benefit,is not beneficent. However, it becomes ethical whenrespecting a fully informed participant’s wish to actaltruistically with the principle of autonomy overridingthe principle of beneficence or non-maleficence.

Assessing net risk is crucial when considering theprinciples of beneficence and non-maleficence. Thedegree of risk acceptable will depend on the importanceof the study, and the capacity of the participant to givefully informed consent. For risk, both the magnitude ofevent and likelihood of the event need to be considered.For example, a high likelihood of minor discomfort suchas bruise with venepuncture may be acceptable, butonly a very low likelihood of more major harm such asdeath may be accepted.

JusticeThe principle of justice implies there should be noinequality in sharing the burden or risks and the ben-efits of research. The most obvious examples of injus-tice are where research benefits or risks are unevenlydistributed amongst the wealthy and poor or conduct-ing research exclusively in minority populations tobenefit non-minority populations.

Merit and integrityThe National Statement emphasizes the concept thatresearch that is of poor scientific merit is unethical.When a participant volunteers or takes risk for a studythey expect the project will generate new and usefulknowledge. Therefore, for a project to be ethical it mustbe scientifically sound with a defined research aim toaddress an important and novel question. The method-ology should also be valid and it should be feasible tocomplete the project as planned to a standard where theresults are valid. For these reasons, ethics committeeswill usually require some evidence of independent sci-entific review and evidence of competency, and resourc-ing. Finally, knowledge is only useful for the publicgood if it is disseminated and published.

Privacy and confidentialityClinical research almost invariably involves the use ofpersonal information. Patients provide information withthe expectation that it will be treated confidentially andthe unauthorized disclosure of such information may bea risk to the subject that should be considered in anyresearch project. Consent to obtain or pass on a person’sinformation should be gained whenever possible.

Similar to medical records in general, patient privacylaws apply to research records. Paper copies of datasheets should be kept in a secure cabinet. The data filesused for analysis should not contain any identifyinginformation such as name and hospital number. Identi-fying information should be kept in a separate pass-word protected file, which should include the uniquepatient identifier assigned in the study that allows theresearchers to link de-identified data back to patients incase they have to contact them. Information technologycan usually set up password protected project directo-ries on hospital computers to ensure privacy and confi-dentiality of identified data.

PlaceboThe use of placebo raises particular ethical issues.Although comparison with no treatment (placebo) maybe preferred to more accurately determine efficacy, it isproblematic to deny a participant a proven therapy ifthere is one available. Thus, placebo is usually onlyused if there is genuine doubt that there is any effectivealternative therapy or if there is genuine doubt that theintervention actually works and there are compellingscientific reasons for using a placebo.

Enrolling subjects who cannot give consentA significant role of the ED is to manage patentsquickly who are unconscious or unable to provide

Research in the emergency department

401© 2010 The AuthorsEmergency Medicine Australasia © 2010 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine

consent. Improving therapy through research is obvi-ously crucial in this important group of patients.However, consent is often not possible as the subject isunable to provide it or therapy must be started beforenext of kin can be found and informed. The NationalStatement4 recognizes this issue and provides guide-lines for when such research can be performed in emer-gency situations without consent. Specifically, any riskor burden of the research must be justified by potentialbenefit to the subject, and there should be no reason tosuspect the participant would refuse consent if theywere able to.

Ethics of research involving children

Over the years, there have been particular occasionswhere children have also been exploited by medicalresearchers.12 Children are also a group where thecapacity for informed consent may be limited. TheNuremberg Code emphasized the importance ofconsent to such an extent that it virtually precludedresearch in children. Guidelines and regulations sincethe Nuremberg Code, including the key Australiandocuments,4,5 all have sections that specifically dealwith children. The age when a child develops the matu-rity to understand, give informed consent or acceptrisk for altruistic reasons is not defined by chronologi-cal age. There will be variability based on complexityof the proposed intervention and the maturity of thechild. The ability to act from moral motivations, suchas altruism, probably develops somewhere around11–14 years of age.13 It is often left to the discretion ofthe ethics committee to set an age at which consent orassent should be obtained and they vary widely intheir recommendation.14

Even though a child may not be able to give fullyinformed consent, many guidelines require some degreeof assent by the child. In other words if a child refuses,that refusal should be respected. However, like consent,the exact age at which a refusal needs to be respected isunclear. Informed consent is usually also required fromthe parents or legal guardians.

There will be (in general) four recruitment scenariosfor children presenting to the ED who may be enrolledin research studies4:1. Infants/toddlers without the capacity to understand

or take part in discussions regarding a researchproject and whose parents/guardians will beapproached for consent.

2. Young children who are able to understand somerelevant information and take part in limited discus-

sion about the research, but whose consent is notrequired. Only parent/guardian consent is requiredfor these children, but the child’s refusal may need tobe respected.

3. Young people of developing maturity, who areable to understand the relevant information butwhose relative immaturity means that they remainvulnerable. The consent of these young people isrequired, but is not sufficient to authorize research,therefore requiring additional parent/guardianconsent.

4. Young people who are ‘mature minors’ who canunderstand and consent, are not vulnerable throughimmaturity in ways that warrant additional consentand where there may be good reason to waive theneed for consent from a parent or guardian.

It is not possible to attach fixed ages to each level in achild or young person, depending on the kind and com-plexity of the project, may be at different levels fordifferent projects.4

As children have limited capacity to consent, thedegree of risk they can be exposed to needs carefulconsideration. In general, risk is classified in degrees,and the degree of risk acceptable will depend on theimportance of the study, and the likelihood of anydirect benefit to the child. For example, the risk of com-plications from placing an intravenous cannula may beunacceptable in a child when studying a minor condi-tion such as otitis media but acceptable in the settingof determining the effectiveness of a chemotherapyagent. In order that some important research involvingchildren may legitimately be carried out, most jurisdic-tions deem that it is acceptable to have some degree ofrisk for the child who is unable to consent where thereis no direct benefit accruing to that child, providedcertain limitations are adhered to. Although the issueof consent in children was addressed in the NationalStatement,4 it still leaves a number of issues open tointerpretation as set out in a recent Australian reviewof the topic.15

In addition, in the ED setting there is the added com-plexity relating to recruitment for a study at the time ofan acute injury or illness. This makes it more difficult tofully assess the child’s maturity level and understand-ing and parents/guardians may be unwilling or unavail-able to consent during the stress of the presentation tothe ED.

Explaining a procedure to a child as part of eitherconsent or assent should always be in terms that thechild can understand, and should take into account achild’s perspective of what is important. Involving a



child in the decision process is an important aspect ofrespect. All attempts should therefore be made toexplain the project and include the child.

Regulatory aspects

At first glance, many regulatory standards appearoverly pedantic, unnecessary or of low importance in aresource scarce research environment such as the ED.Indeed in some respects, some regulatory guidelines doset a very high bar primarily aiming to ensure data arehighly verifiable and thus preventing fraud. Some arealso set somewhat arbitrarily so that regulatory authori-ties can have some globally uniform level of quality,which they can accept as sufficient to set drug labellingor make other regulatory recommendations with a highdegree of assurance that these recommendations arebased on verifiable and trustworthy evidence. Of course,one obvious argument for following these standards isthat regulatory or other authorities say we have to.They are ‘the law’. If you do not follow them you mayrisk losing funding or prosecution. These, however, arethe lesser arguments for following these standards. Byfar the most important reason is the science. Goodquality research conducted to a high standard is mostlikely to answer important research questions with trueanswers. Low quality research tends to only capture the‘low hanging fruit’, wastes money, answers only theirrelevant questions or most worryingly, misleads clini-cal practice.

Good clinical research practice in Australia is basedon the principles set out in some key documents, whichaim to guide institutions and researchers in how todevelop and sustain responsible research practices. Thekey Australian regulatory documents for all research inAustralia must abide by are the ‘National Statement’(see ‘Important documents for Australian researchers’)as developed by the peak medical research bodies inAustralia,4 which in turn requires that research isconducted in accordance with the ‘Australian Code’ ofConduct5 (see ‘Important documents for Australianresearchers’). These documents do not provide anexhaustive description of how to conduct research. TheTherapeutic Goods Administration (TGA) has pub-lished a more detailed document describing howresearch should be performed in Australia, which inturn requires that researchers follow relevant sectionsof the International Conference on Harmonisation GoodClinical Practice (ICH-GCP) guidelines.16 Thus in somecircumstances, such as drug trials with Clinical Trial

Notification, a process by which the TGA must be noti-fied about a drug or device trial, there is a clear regu-latory requirement to follow particular and detailedregulatory standards, whereas in other circumstancesthe requirements are not so directly stated.

Important documents for Australian researchers

1. National Statement on Ethical Conduct in HumanResearch4 – a joint NHMRC/Australian ResearchCouncil (ARC)/Australian Vice Chancellors’ Commit-tee (AVCC) revision of the 1999 National Statementon Ethical Conduct in Research Involving Humans.This is Australia’s primary source of guidance pro-moting ethically sound review and conduct of humanresearch with national standards to guide institu-tions, researchers and HREC. This recently reviseddocument particularly ascribes essential governanceresponsibility to the institution, distinct from theethical review and HREC reporting requirements forprojects.

2. Australian Code for the Responsible Conduct ofResearch5 has been jointly authored by the ARC,the AVCC and the NHMRC. It is designed to guideinstitutions and researchers in how to achieve andmaintain responsible research practice. The codeaddresses the role of institutions in establishingresearch policies that promote high standards ofresearch integrity and an environment in whichresearch will be conducted responsibly.

3. International Conference on Harmonisation GoodClinical Practice (ICH-GCP) guidelines17,18 is an inter-national document also accepted in Australia. It is anoverarching ethical and quality standard for thedesign, conduct, performance, recording, analysis,monitoring, auditing and reporting of clinicalresearch. The ICH was born in 1989, developedthrough a drive to regulate requirements for a singlemarket for pharmaceuticals. ICH-GCP is also knownas GCP or GCRP. It also includes protection ofhuman rights as a subject in a clinical trial.

The aim of these documents is not only to increase thescientific quality and hence the veracity of the findingsbut also to ensure research is conducted in an ethicallyresponsible manner and that the findings are verifi-able. Being compliant with these documents assuresthe public that the data and reported results are cred-ible and accurate and that the rights, integrity andconfidentiality of human research subjects have beenprotected.



Getting approval: the ethicsreview process

The implementation of national guidelines and prin-ciples to individual projects is left to the discretion ofcommittees administered locally by research institu-tions or hospitals. This is because situations often arisewhere there may be tension between competing prin-ciples, or judgments need to be made on acceptable risk.Research other than low or negligible risk research mustbe reviewed by an ethics committee. Ethics committeesare usually composed of representatives from clinical(doctors, nurses etc.), research and community (laypeople and clergy) groups. All research must beapproved in writing by the sponsoring institution beforeit can commence. Research requiring HREC approvalmay not start until there is clear written approval fromthe committee.

The primary objectives of an HREC are to assess theethical principles by which research projects in humansare proposed and conducted, protecting the welfare andrights of the research participants and to facilitateresearch that is, or will be, of benefit to the researcher’scommunity or to humankind. HREC may also considerall matters relating to project design, technical feasibil-ity and any other ethical implications associated witheach project. The ethics review process is not perfectand may be frustrating but a wise researcher engageswith the ethics committee in a positive and helpfulmanner.

Confusion sometimes arises with quality assurance(QA),projects or audits such as the review of extantmedical records.19,20 In the Australian setting, NHMRCspecifically addressed the issue in a 2003 publicationtitled ‘When does quality assurance in health carerequire independent ethical review?’20 which is stillreferred to in the recent National Statement.4 In thiscontext, the term quality assurance incorporates theterms quality improvement, quality activities, qualitystudies, audit and peer review. It notes that there are noclear definitions separating ‘quality assurance’ from‘clinical research’ and that both form a continuum.Although QA should be encouraged to improve healthcare and minimize adverse events, patient interests andprivacy need to be protected to prevent inadvertentexposure to risks. QA should use valid methodologyand tools and must be conducted within the legal frame-work of state and commonwealth legislation. The docu-ment provides a number of detailed questions (in termsof consent, risks and burden, privacy etc.), which if allanswered in the negative will confirm a QA status and

negate the need for HREC approval. Institutions areencouraged to establish policies to allow the efficientreview of QA projects without full HREC review.However, a number of institutions have folded QAprojects into the HREC approval process. Rather thantrying to delineate QA and research, it may be better toconsider them both in terms of risk, burden, privacy etc.,in which case QA is usually treated the same way asnegligible risk research where consent is almost alwayswaived and the project is reviewed in a process outsidefull HREC consideration. QA should be treated the sameway in all other aspects of standards of research. Find-ings from an audit often do have a wider application,and the publication of QA projects can provide valuableadditions to the literature on improvements in care andpatient safety. Many journals will require HRECapproval before publication. For QA projects withoutsuch approval, the relevant HREC may supply a state-ment for the editor that the project was carried outaccording to NHMRC guidelines.20 Treating QA projectsfrom the outset as HREC approved negligible riskresearch obviates the need for such retrospective assess-ment and approval.

HREC approval is often contingent on other pro-cesses. The hospital lawyer and hospital insurer mayhave to sign off on high risk projects; the trials mayneed registration (see Part II of this series) and TGAnotification21 may be required in clinical drug or devicestudies. Only HREC approved study documents may beused during a study.

HREC approval is often associated with mandatoryreporting requirements in terms of adverse eventsduring the study (see Part II of this series) and forinterim and final reports after completion of the study.In some states, applications for ethics approval requirethe use of a statewide ethics approval form as its basis,often complemented by institutional forms. The Austra-lian Health Ethics Committee has developed a web-based National Ethics Application Form (NEAF)22 tocomplete standardized research ethics proposals forsubmission to HREC. This would be particularly attrac-tive for multicentre applications. However, a unifiedapproval process does not always result in an easier orfaster ethics review process..23,24 Our experience in mul-ticentre research within an Australian and New ZealandED research network (Paediatric Research in Emer-gency Department International Collaborative) indi-cates that the time and effort required – even usingNEAF – multiplies with additional sites and is easilyunderestimated in terms of time and resources required.We found the following steps helpful: (i) providing



documented HREC approval at one of the larger keysites to HRECs at other sites early on appears to speedapproval at other sites; (ii) it is crucial to track all pro-tocol versions at all sites and number them consecu-tively; (iii) after formal approval at all sites, it is helpfulto create a common version of all study documents to beapproved by all sites as an amendment – this allows allsites to use the same version; and (iv) to ensure compli-ance with the ethics process and provide a uniformstudy approach it is crucial to ensure the use of thecorrect versions of the study documents.

Research misconduct

Although the term ‘breach’ describes less serious devia-tions from the Australian Code for the ResponsibleConduct of Research,5 the term ‘research misconduct’ isused for more serious or deliberate deviations. Problemsrange from interfering with the study processes, forexample, the opening of randomization envelopes beforeenrolling patients to outright fabrication of results.Research misconduct is a serious matter with conse-quences beyond endangering the participant in a studyand results that may falsely lead to a change in therapyof a great number of patients. Research misconductjeopardizes the reputation of researchers, institutionsand the entire research endeavour. Research misconductdoes not include differences in interpretation of or judg-ments about data. Further information regardingresearch misconduct, responsibilities and the manage-ment of complaints and allegations are set out in theAustralian Code for the Responsible Conduct ofResearch.5

Summary

Research must be conducted ethically and to a rigorousstandard. The ethics principles underlying all EDresearch are respect for persons, beneficence, justice aswell as merit and integrity. Consent and risk are keyethical issues to be addressed in all studies. The stan-dards of rigour in research conduct are set out in theprinciples of GCRP. Although in many cases it ismandatory to follow these regulatory documents, fol-lowing them also provides greater assurance that theresults are actually true, and that the results have notbeen intentionally, or more commonly unintentionally,corrupted.

Acknowledgements

We acknowledge grant support from the Murdoch Chil-dren’s Research Institute, Melbourne, Australia, indeveloping the materials and teaching tools for GCRP.Some of the concepts and information contained in thispaper are based on a lecture series titled ‘Introduction toClinical Trials’ and materials for Advanced Medical Stu-dents developed by the Clinical Epidemiology and Bio-statistics Unit, research orientation materials by theClinical Research Development Office and administra-tive and education materials produced by the EthicsResearch Office at Royal Children’s Hospital, Mel-bourne, Australia. We acknowledge Ms Lisa Sharwoodfor her contribution to developing GCRP materials atthe ED at Royal Children’s Hospital.

Competing interests

None declared.

Accepted 22 June 2010

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Documents

A primer for clinical researchers in the emergency department: Part I: Ethical and regulatory background