The Quality Assurance JournalQual. Assur. J. 2: 167–172 (1997)

Defining Quality in the EthicalReview Process

Public confidence in the quality ofthe ethical review process ofmedical research is critical to amore general confidence in medicalresearch itself. Systems for suchreview have developed rapidly inmany countries in recent decadesand decisions can be based onclear statements of principle, suchas the Declaration of Helsinki, andnational and international guidelines,such as those produced by theCouncil for InternationalOrganisations of Medical Sciences inassociation with the World HealthOrganisation. Ethical decisions,however, are often not clear cut, sothat measurement of quality bystandard methods of audit isinsufficiently sensitive. This articleidentifies key components of an

ideal system for ethical review andexamines five areas of activity thatcould be used as pointers to qualityand would be amenable tocomparative reviews.

© 1997 John Wiley & Sons, Ltd.

INTRODUCTION

Medical research enables the verification of theefficacy and safety of both established and novelprocedures used in clinical medicine. However,while most physicians regard medical research asan essential component of optimal health care,such research has not always enjoyed the fullconfidence of the public, whose interests’ it isdesigned to serve. The aim of this contribution isto show how the development of quality measuresfor the independent ethical review of researchprotocols might contribute to a culture wheremedical research is regarded as an ethical andpositive element of healthcare.

In our multicultural society, rule-based (deistic)ethics are the exception rather than the rule; ethi-cal issues are by their very nature open to discus-sion and debate, but are not amenable to absolutedefinition or resolution. Indeed, they are probablynot so in strictly deistic systems, such as those ofJudeo–Christian or Islamic religions. Definingquality and auditing against agreed standards will,therefore, be extremely difficult. Nevertheless, ithas been possible to reach general internationalacceptance of certain principles and these havebeen embodied in codes and declarations acceptedby virtually every member of the UN.

The concepts of non-malificence and informedconsent were first established, not by the researchcommunity but, by law in Germany in the late19th century [1]. Further, these judgements clearlydistinguished between therapeutic and non-thera-peutic research, allowing the former to proceedwithout explicit subject consent in medical emer-

John Trippa,b,*,1

a Senior Lecturer in Child Health,Postgraduate Medical School,University of Exeter, Church Lane,Heavitree, Exeter EX2 5SQ, UKb Consultant Paediatrician,Royal Devon and Exeter Healthcare NHS Trust,Royal Devon and Exeter Hospital (Wonford), Barrack Road,Exeter EX2 5DW, UK

* Correspondence to: Senior Lecturer in Child Health, Postgrad-uate Medical School, University of Exeter, Church Lane, Heav-itree, Exeter EX2 5SQ, UK.1 Tel.: +44 1392 403154; fax: +44 1392 403158; e-mail:j.h.tripp@ex.ac.uk

CCC 1087–8378/97/040167-06 $17.50© 1997 John Wiley & Sons, Ltd.

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gency situations, and recognised the possibility ofabuse of privilege that might arise when subjectswere in dependent relationships with investiga-tors. Whether such laws were widely applied byphysicians and researchers at that time is nowdifficult to establish, but it was the abuse of theprinciples by physicians in Nazi Germany that ledto the Nuremberg trials and the publication of theNuremberg Code in 1947, with ten standards towhich physicians must conform when carrying outexperiments on human subjects. Subsequently, the18th World Medical Assembly in 1964 adopted adeclaration acknowledging the duties of doctorsembodied in the Geneva Convention to keep theinterests and needs of their patients as their firstconsideration; but, recognising that medical re-search is often inevitably associated with risk, laiddown a framework of standards for ethical medi-cal research [2]. The Declaration of Helsinki remains,with minor revisions at subsequent Assemblies,the key international document against which theethics of medical research are judged in interna-tional fora. A more radical revision of the struc-ture, but not the content, of the Declaration iscurrently in draft form and is undergoing interna-tional consultation. The near universal acceptanceof these principles by the international commu-nity, representing countries where a variety ofmoral and religious codes operate, suggests thatthey are sufficiently robust to form the basis for anassessment of the ethics of medical research appli-cable to the whole of humanity.

‘‘. . . systems available for the reviewof the ethics of medical researchhave not always measured up tothe quality required to providepublic assurance that thestandards of the Declaration ofHelsinki are. . . . . . .operative’’

There is, however, ample evidence in several legaljurisdictions and in the medical literature, thatthese precepts were not always adhered to after1947, after 1964, nor are universal in practice evenin the present day. For example, an issue thatstands out in the literature of recent decades is thenon-availability of best-known treatment to partic-ipants in the placebo-controlled trials often re-quired by regulatory authorities, or sometimes intrials where subjects have been in dependent rela-tionships, such as prisoners or members of armedforces. This in turn suggests, that the systemsavailable for the review of the ethics of medical

research have not always measured up to thequality required to provide public assurance thatthe standards of the Declaration of Helsinki areindeed always operative.

While the principles may be generally accepted,the detail of their application is not always clearlyresolvable. Some issues continue to cause publicdebate. Current controversies include the use ofmedical records and biological specimens for re-search without individual consent, the availabilityof the best standard of known treatment to ThirdWorld subjects in drug trials for HIV/AIDS, andthe level of understanding required for genuineconsent.

The intention of this article is to be illustrativerather than conclusive. As an approach to definingquality in a system where absolutes are difficult todefine and measure, set out below is a personaldescription of what an ideal ethical review systemmight look like (restricting the area of interest tomedical research involving human subjects), andthen examine some areas where existing systemshave experienced difficulty.

AN IDEAL SYSTEM FOR THE ETHICALREVIEW OF MEDICAL RESEARCHINVOLVING HUMAN SUBJECTS

Ethical medical research will include researchwhere the aim is to advance the understanding ofhuman biology, health or disease and will often bedirected towards improving treatments availablefor illness or disability. It would be hard to im-prove upon the guidelines published by the Coun-cil for International Organisations of MedicalSciences (CIOMS) [3] as valid principles on whichto base the evaluation of the ethics of a researchproposal. What follows is entirely consistent withthese. An ideal ethical review system would sup-port and encourage ethical medical research in theinterest of humanity, while ensuring that the re-search meets the standards of the Declaration ofHelsinki. In order to achieve this, it is suggestedthat the review would have included considerationof all the issues embodied in the CIOMSguidelines.

The ideal ethical review process will, before re-search is undertaken, provide public assurancethat the research:

� addresses an issue of scientific importance thatrequires human participants;

� is beneficent and not predominantly motivatedby profit or gain;

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� is to be carried out by appropriate personnelusing valid methods that will produce meaning-ful results;

� involves known levels of risk that are min-imised to the greatest possible degree;

� respects participants and includes measures tomaximise safety;

� has clear and robust arrangements for compen-sation in the case of an adverse event;

� provides participants with full information anda genuine opportunity to opt-in, or not, as theychoose, and as far as they are able;

� and that the process of review is fair and doesnot unnecessarily impede the progress of ethicalresearch.

‘‘The process of independent reviewis thus integral to, and supportiveof, the research process. . . . . . ’’

It is highly desirable that the review systemshould develop a culture of ethical research amonginvestigators and sponsors. Such a culture of ethi-cal research might be expected to result in im-provements in:

� public appreciation of the importance of medi-cal research in the provision of high quality andimproving healthcare, so that research would beperceived as an essential component of an ethi-cal healthcare system;

� public understanding of the ethical issues raisedby research, where individuals may be asked toparticipate in research for the benefit of othersand accepting some level of ‘no benefit’ tothemselves;

� the research community’s acceptance of the es-sential role of an independent ethical review ofresearch protocols;

� public confidence in the efficacy of the ethicalreview process in protecting participants frominvolvement without appropriate informationand consent procedures.

Thus, the process of independent review is inte-gral to, and supportive of, the research process,encouraging participation by subjects in an en-deavour that has enormously accelerated the abil-ity of health services to alleviate suffering andprolong life. Failure to provide public confidencein the ethical nature of medical research would notonly substantially undermine opportunities formedical advances, but result in a more general lossof confidence in the provision of medical care withadverse consequences for a nation’s health.

RECENT HISTORY OF THE ETHICALREVIEW PROCESS

Publicly accountable and independent review ofmedical research proposals to achieve public as-surance are relatively new processes (of the lastthree decades), which is still developing rapidly inmany countries and at an early stage in others. Atfirst sight the duties of an independent reviewcommittee appear straightforward, and as readilyagreeable to the research community as to thosewho drafted and have subsequently updated theDeclaration of Helsinki. In practice, however, theapplication of the Helsinki Declaration is compli-cated both by the fact that different standardssometimes appear to conflict with each other andthat the setting up of publicly accountable systemsthat do not impede research has proved difficult.A formal review of all medical research has gradu-ally become more robust and publicly visible sincethe development of guidelines (e.g. those of theRoyal College of Physicians of London) [4], na-tional systems of review, and legal or contractualrequirements.

This article addresses the basic requirements enun-ciated above, emphasising situations where reviewsystems may experience difficulty in achieving anappropriate balance between aims and expecta-tions that appear to be in conflict with each other.It is not the aim of this paper to discuss therequirements that should be met in protocols,forming the substance of the consideration by acommittee. That area is well-covered in many na-tional and international guidelines. The require-ments will be considered under five mainheadings: (1) public assurance, (2) meeting theneeds of the research community, (3) education ofresearchers and the public, (4) audit of proposals,and (5) education of members and audit of theiractivity.

PUBLIC ASSURANCE

Public assurance that medical research is beingconducted in an ethical manner requires guaran-tees that participants will be respected as individu-als, will be appropriately consulted, will be offereda free choice of participation, will be aware of thedegree of risk and benefit to which they are to beexposed, and will be both maximally protectedfrom those risks and ‘insured’ against adverseoutcomes. This requires that the ethics committeeis set up and functions in a transparent and ac-countable fashion, and has among its membersthose who are adequately informed and able to

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make judgements on their behalf. Local account-ability is seen in some countries to be particularlyimportant in assuring that the personnel and re-search facilities are appropriate and that the indi-viduality of the local community has receivedsufficient consideration.

In practice this means that committees will need tobe publicly appointed by a body whose maininterest is in the health of the population and notin research. The committee should make an annualand publicly available report to this body. Further,the appointing authority must, having agreed ap-propriate standing orders to ensure the good oper-ation of the committee, give it complete freedomof action and not attempt to influence its decisionsfor fiscal or other reasons. Standing orders willcover such issues as appointment of members andchairmen, frequency and structure of meetings,quorums and voting arrangements, actions thatmay be agreed by postal working or chairman’saction, etc. The current practice in most countriesis that members receive no financial reward fortheir participation in committees. While providingassurance that members’ motivation is not finan-cial, this may also mitigate against the participa-tion of potentially valuable members; onimportant committees with high work loads, abalance may need to be struck. Members, particu-larly lay persons, need the assurance that if theyinadvertently approve a proposal that is flawedand results in personal injury, any legal liability isborne by the employing authority or is covered byan appropriate insurance policy.

Committees will need to be of sufficient size toenable members to have between them, the varietyof scientific and other skills required to make fairand valid assessments of proposals. This assess-ment must include evaluations of the possiblevalue of the research to subjects or to human kind,the risk or disadvantage to which subjects areexposed, and the scientific credibility of the re-searchers and their methods, including statisticalanalysis. While committees, in order to providethis expertise, may include persons heavily in-volved in research, these must be balanced byother informed professionals who can be seen asadvocates for patients and other participants, suchas nurses and general practitioners. They also needto have uninvolved lay persons among their mem-bership, with representatives of both genders and,where appropriate, of ethnic or other minoritygroups. While it is considered that the assessmentof ethics is a matter for the ‘man or woman in thestreet’, it is often beneficial to have a person whois trained in the evaluation of ethical issues, such

as a religious leader, and also to have the benefitof legal advice in relation to issues such ascompensation.

‘‘. . . it is important that thecommittee is ‘user friendly’ and theuser is in fact the researcher.’’

MEETING THE NEEDS OF THERESEARCH COMMUNITY

If it is accepted that medical research is in the bestinterests of the population, then it is importantthat research ethics committees not only protectthe public but support and encourage good medi-cal research. If researchers are to use review pro-cesses without the need to do so under duress,then it is important that the committee is ‘userfriendly’ and the user is in fact the researcher.Delayed responses, complex and highly variableapplication forms and procedures, together withfailure to allow researchers answer what is occa-sionally ill-informed criticism or misunderstand-ings of proposals, has in the past been the cause ofmuch criticism of committee relations with re-searchers. Most are relatively easily addressed bycarefully formulated standing orders, supportiveadministrative arrangements for committees, stan-dardised application forms, and other measures.

It is to be expected that individual committeesmight come to different conclusions about thefiner ethical points of a proposal. However, if thestandards of the international conventions areagreed as a valid basis for decisions, fundamentaldisagreement should be rare. It has been sug-gested that having powerful individuals on unbal-anced or poorly constructed committees results indecisions that would not be supported by othermore balanced considerations [5]. Many commit-tees do not refuse approval for a proposal withoutgiving the researcher the opportunity to appear inperson to answer criticism. In some national sys-tems there is an established process of appeal byresearchers to a different or higher levelcommittee.

Certain special research situations mitigate againstthe easy consideration of proposals by a locallybased committee. Failure to address the ethicaland scientific concerns of these situations to thesatisfaction of committees and researchers has, inthe past, led to much frustration and even resultedin the suggestion that some types of research need

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Defining Quality 171

not be submitted for independent review [6].These include firstly, multicentre or multilocationtrials, where, for scientific validity, there is a needfor a consistent application of single protocol in allparticipating centres, potentially in several coun-tries; and secondly, proposals where an individualclinician may enter very few or no patients, suchas trials of therapy for rare malignancies in chil-dren where immediate entry is a treatment neces-sity. An ideal ethical review system might providea centralised review of such protocols with theopportunity for local committees to review aspectsof the protocol of particular local relevance, suchas premises, personnel, and the language of pa-tient information and consent forms. Other possi-bilities are the use of chairman’s action (laterratified by the committee) or ‘class approvals’ for agroup of potentially similar research protocols ful-filling certain agreed criteria that might be applied,e.g. as a solution to the rare entry type of protocol.

EDUCATION OF RESEARCHERS ANDTHE PUBLIC

Ethical review committees have a significant op-portunity to contribute to improving the quality ofmedical research by education of the researchcommunity. They can also educate the public as tothe value of participation in the interest of thegood of mankind. They may provide researcherswith good practice guidelines for the wording ofparticipant information and structure of consentforms, as well as check lists of pro-formas forapplications, which alert them to the issues to bediscussed. Many committees invite a proportionof, or even all, applicants to part with their delib-eration. Others provide an inquiry service to appli-cants that is educational.

They may provide lectures to undergraduate andpostgraduate students in relevant disciplines. Byconsideration of student projects, they may em-phasise the importance of ethical review and givethe students the opportunity to experience thedrafting and submission of protocols. The ethicalmandate for student research is an opportunity forpublic education about the ethical review processas part of the necessary training of students tocarry out research. Similar opportunities may bepresent in institutions where members of profes-sions allied to medicine are required to carry outresearch projects for postgraduate qualification orcontinuing professional development. Publicationof an annual report is an opportunity for publicrecognition of the volume and importance of localresearch activity.

AUDIT OF PROPOSALS

Many structures provide for a certain amount ofaudit of the proposals coming to a committee. Atits simplest level, this might simply be an analysisof the number of proposals approved, approvedafter modification and not approved in the annualreport. Many committees require applicants tosubmit annual and/or final reports of their re-search, together with a list of publicationsachieved or planned. In some countries, includingthe UK, registers of research activity are collectedwith the assistance of research ethics committees,and this register is used to ensure recording ofresults from unpublished work with the benefit ofcorrecting publication bias against negativefindings.

Some committees may see their auditing activityextending to making some of the checks that areassured in sponsored therapeutic trials by trialmonitors, but are often not applied in university orcharitably funded research. These include checkson data management and control, data protectionregistration, completion and retention of consentforms, etc.

EDUCATION OF MEMBERS AND AUDITOF THEIR OWN ACTIVITY

Quality in the process of ethical review cannot beachieved without the continued development ofskills by members of committees. Formal educa-tion for new members in the process of ethicalreview and for lay persons in the language andprinciples of research methods may make a sub-stantial contribution to the quality of the process.Meeting together to discuss proposals that havebeen pre-reviewed by individual members is alsoa major mechanism in the development of individ-uals skills, and regular meetings are essential; incontrast to the many committees who until rela-tively recently conducted much of their businessby post. Members need to serve on a committeefor a significant period, perhaps minima of 30meetings and consideration of 100 protocols. Com-mittees need to be appointed on a rotating basis sothat not too many new members join at any onetime.

In some countries there are hierarchical structuresof research ethics committees, so that committeeswith greater experience can advise and therebycontribute to the development of smaller commit-tees; while in others, the individual nature ofethical decisions has resulted in the local commit-

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tees having complete autonomy. Occasional na-tional meetings of chairmen or regional meetingsof committee members serve as useful fora formutual education and discussion of topical or con-troversial issues.

Self audit of the timeliness of responses in commit-tee activity is practised by many committees andrequired by appointing authorities as part of theannual report. Some authorities have suggestedformal comparison of committees’ decisions usingdummy or multiple applications to committeeswith the same protocol and the literature containsseveral reports of researchers experience of multi-ple application for multilocation protocols.

DEFINING QUALITY IN THE ETHICALREVIEW PROCESS

In conclusion, it is suggested that, in spite of thefact that the definition of absolutes in this area isunrewarding, there are a number of ways in whichthe quality of the ethical review process could beevaluated against as many or as few of the possi-ble indicators of quality derived from the aboveparagraphs as desired. Such evaluations could

form the basis of a robust system of audit ofmedical research ethics conducted against anagreed international standard, The Declaration ofHelsinki. This would make a positive contributionto the development of public and governmentalconfidence in both the ethics and value of medicalresearch in health provision, and contribute to aworld culture of ethical medical research.

REFERENCES

1. Vollman, J. and Winau, R. Informed consent in humanexperimentation before the Nuremberg code. British MedicalJournal 1996; 313: 1445–1447.

2. The Declaration of Helsinki of the World Medical Association1964, revisions published in 1975, 1983 and 1989, and afurther revision is currently under discussion in 1998.

3. Council for International Organisations of Medical Sciences(CIOMS) in association with the World Health Organisa-tion (WHO). International Ethical Guidelines for BiomedicalResearch Involving Human Subjects, Geneva: CIOMS andWHO, 1993.

4. Guidelines on the Practice of Ethics Committees in MedicalResearch Involving Human Subjects. London: The Royal Col-lege of Physicians of London, 1996.

5. Foster, C. Why do research ethics committees disagree witheach other? Journal of the Royal College of Physicians of London1995; 29: 315–318.

6. Independent ethical review of studies involving personalmedical records. Report of a working group. Journal of theRoyal College of Physicians of London, 28: 429–443.

© 1997 John Wiley & Sons, Ltd. Qual. Assur. J. 2: 167–172 (1997)