Research ethics committees: what can we learn from the Western European and United States experience?

Monash Bioethics Review Vol. 20 No.2 61 Ethics Committee Supplement

Research ethics committees: whatcan we learn from the WesternEuropean and United Statesexperience?

ROWANFREW

The Alfred Hospital, Melbourne

INTRODUCTIONReview of human research and the role of Human Research

Ethics Committees (HRECs) in Australia is guided by the NationalHealth and Medical Research Council's (NHMRC) National Statement onthe Ethical Conduct of Research Involving Humans (1999). The NationalStatement makes reference to the HREC research project reviewprocess and the requirement for monitoring of research as a means ofprotecting the participants of research. Over the past ten years, therehas been an increase in the number of research applications to HRECsand this, along with the requirement to review and monitor projectsmore closely, has resulted in a much-increased workload on HRECs.The workload has increased to the extent that it is now questionablewhether HRECs can adequately conform to the review and monitoringrequirements of the National Statement.

With this in mind, the author visited The Netherlands, France,the United Kingdom and the United States of America. The main thrustof the trip was to discuss first-hand the research review process,methods of monitoring of research and funding of HRECs and theirsecretariats. The information on overseas research ethics committeesprovided in this paper was obtained through the interviews, unlessreferenced to written articles.

Through the overseas experience, the author will attempt toprovide some realistic suggestions to health authorities that mayovercome some of the current difficulties that face Australian HRECs intheir review of human research.

THE TRIPThe four countries visited were chosen for the following reasons.

It was thought that the European countries would provide enoughvariation in population and area size, and differing cultural attitudes,to gain a balanced view of operations in the Western tradition. TheUnited States of America was included because of the influence thatcountry has in Australia through commercially sponsored clinicalresearch. Most of the institutions chosen had large research ethicscommittees which reviewed a diverse range of research projects.

Monash Bioethics Review Vol.20 No.2 62 EthicsCommitteeSupplement

The countries covered in this paper will be, in order, TheNetherlands, France, United Kingdom and the United - States ofAmerica. A comparison of structure, review and monitoring of research,and financial and funding issues will be made.

THE NETHERLANDS

Background and structureTwo centres in The Netherlands were visited, the University

Medical Centre, Utrecht and the Institute of Bioethics, Maastricht. TheUtrecht centre is a large university hospital with about 400 newresearch applications per year. The Institute of Bioethics in Maastrichtexists as an independent foundation, with support from the EuropeanCommission and the Maastricht University. The Institute, amongstother things, specialises in formulating policies, such as genetics andreproductive technology, long term care, particularly in the elderly andthose with psychiatric illness, and resource allocation. The Institutealso considers significant ethical issues associated with research, suchas the consent process.

A new central supervisory human research ethics committee, theCentral Committee on Research Involving Human Subjects (CCMO) 1

has been set up in The Netherlands as a result of new legislationintroduced in December 1999. The CCMO has several functions:• to approve the composition and credentials of local Medical Ethics

Review Committees (METCs)• to consider research issues in general• to act as a review committee for particular high-risk studies which

are referred to it by the METCs . These mostly involve research inchildren and those who cannot consent, and other projects withsignificant ethical issues, such as gene therapy research andxenotransplantation

• to advise on research involving human embryos and gametes.The CCMO also has the authority to overturn METC decisions

regarding research review.There are about eighty METCs in the Netherlands, all reporting

to the CCMO. They are legal entities, independent of the institutions towhich they are associated, and their decisions are open to appeal.

When the new legislation was introduced, it specified thecomposition of METCs and for the first time there was lay membershipto represent participants of research. Membership of MTECs includes:• at least one lay person of either sex• at least one physician• at least one 'ethicist' 2

• at least one lawyer• at least one epidemiologist• and possibly a nurse, a psychologist or a pharmacologist.


Review of research: scope of authority, functionsand processes

The CCMO has its own ethics application form, as does eachMETC, although the CCMO is designing a common form to be used byall applicants.

In the past, problems have existed with review of multicentreresearch by each HREC involved, mainly to do with:• different levels of insurance• different standards expected of applications• different ways of conducting research.

To overcome these difficulties, multicentre trials are considered andapproved by a main centre (not necessarily the CCMO) which is chosenby the sponsor or individual researcher. . Once approval is given,participating METCs may decide on variations, usually to the PlainLanguage Explanatory Statement for participants. The Board ofDirectors at each site approves the suitability of the site to conduct thestudy. Most of the large university hospitals still prefer to review eachapplication themselves, regardless of which is the principal site. Thereviewing centre, or principal site, varies, and does not need to beapproved as a principal site by the CCMO.

The CCMO is sent a copy of every METC's decision, whether theproject has been approved or not.

Because of the large number of projects at the Utrecht centre,its METC is divided up according to the type of application and eachhas its own membership. Turnaround time for review is about four tosix weeks, but can be as short as two weeks. Each member of thecommittee reviews each application, with certain members beingallocated certain projects for detailed review.

Monitoring of researchThe new Dutch law requires progress reports on approved

studies to be submitted at least once a year.At the Utrecht Medical Centre, audits of research projects are

not conducted, It is not known whether this is done in otherinstitutions. Adverse events and protocol amendments are consideredonce a week at a meeting with the chair and a selection of othermembers. Significant serious adverse events and amendments arereferred to the METC. For clinical trials involving new drugs, all SAEsare sent to the government authority.

The CCMO is notified of amendments and the prematuretermination of projects. It is also informed of SAEs, but only whenreally relevant and results in a change to the Plain Language Statementfor participants.

Financial and funding issuesAt the Utrecht centre, no fault insurance is taken out for

researchers. This insurance provides protection for the researchersand, should mishap occur, participants would be compensated.


The financing of research projects is reviewed and approved bythe management of each area where the research is to be held. At theUtrecht centre, single-centre commercial studies attract a review fee of2000Nfl (approx. A$1700), and multicentre studies 5000Nfl (approx.A$4200). Other studies not associated with the Centre are charged2000Nfl. Fees to cover infrastructure costs of institutions, andamendment fees, are currently under review at the Centre.

METC members not associated with the Centre are paid fortheir involvement, but not to an excessive degree. Volunteers forresearch and patients are paid along much the same lines as inAustralia, that is, for time and inconvenience.

FRANCE

Background and structureThe Agence Francaise de Securite Sanitaire des Produits de

Sante (AFSSaPS) was visited. The AFSSaPS evaluates all newbiomedical devices and has a role similar to the Therapeutic GoodsAdministration (TGA) in Australia. It reports to the French Ministry ofHealth.

The author also visited the former president of the researchethics committee of Hopital Paris Cochin. The Hopital Paris Cochin is alarge public hospital in central Paris and has for many years beenprominent in ethics and the review of research. It started up anunofficial research ethics committee in the 1980s and was one of thefew available up to 1991 to give advice to researchers on the ethics ofmedical research.

A National Advisory Committee on Ethics was created in the1980s and looked at ethical problems in areas such as IVF, but therewere no official committees for review of biomedical research. The firstresearch ethics committee was set up in 1991 and called the ComiteConsultatif de Protection des Personnes se Pretant a la RechercheBiomedicale (Consultative Committee for the Protection of Persons whoUndertake Biomedical Research) (CCPPRB).

In 1998 a new law, the Lei Huriet (Huriet Law) was created tofurther protect those involved in biomedical research. Although the lawprimarily covers biomedical research, it can be applied to other types ofhuman research, such as in the socio-psychological sciences. The lawexists to protect participants of research through standards set for theutility of the research, the scientific rigour, conformity with goodclinical practice guidelines and the suitability of the research site.

Like Dutch research ethics committees, the CCPPRBs operateseparately from hospitals, although they largely exist within them.CCPPRBs exist within regions and researchers may apply to anyCCPPRB within a region for ethics approval, even if it is not where theirown research is being conducted. France has twenty-six regions, withabout forty-eight CCPPRBs overall. Each region has between one andtwenty CCPPRBs. The Paris region has about fourteen CCPPRBs.


CCPPRBs require a minimum of twelve members, with up toanother twelve alternate members, with a balanced membership. TheParis-Cochin HREC membership includes:• four people involved in medical research (at least three physicians)• at least one general practitioner• at least one nurse• two pharmacists (at least one from the hospital and if necessary,

one from the community)• four others• at least one ethicist• at least one social worker• at least one psychologist• at least one lawyer• lay and medical people.

There is no requirement for a minister of religion, but an 'academic'ethicist is included in the membership.

Review of research: scope of authority, functions andprocesses

Application for ethics approval is made to the CCPPRB, which isgiven the Plain Language Statement, Consent Form, protocol and safetyinformation for review. There is no common ethics application form,although many other CCPPRBs have adopted the Paris CochinHospital's form. Each CCPPRB has its own working procedures.Approval is given by a CCPPRB in the region in which the chiefresearcher works. Institutions in regions without university hospitalscan seek approval from another region 's CCPPRB if it is consideredappropriate by the institution's administration. The chief researchermust be a physician and is the person responsible for the quality of theresearch, for patient safety and for the information given toparticipants.

In multicentre s tudies, review by one CCPPRB only is required.The CCPPRB is chosen by a sponsor or by individual researchers. If acentre has too many projects to review, it can refuse them or postponereview until later than the mandatory five-week review period, in whichcase the sponsor can choose to go elsewhere. When there are severalinvestigators wishing to conduct the same research at different sites, aresearch coordinator is designated to apply to the CCPPRB forapproval. CCPPRBs must give a response within five weeks of receipt ofthe submission. Four more weeks can be authorised if questions areasked of the researchers or the sponsor. Only the CCPPRB reviewingthe project has the application details - CCPPRBs of participating siteshave no involvement in the review process.

At Paris Cochin, the CCPPRB chair nominates one or tworeviewers for a detailed report on the project - typically one to provide ascientific report and the other to review the Plain Language Statementand consent procedures. The scientific reviewers do not need to bemembers of the CCPPRB. There is no approval period, but the CCPPRB


can ask for progress reports at intervals appropriate to the risk of theresearch.

Unlike new drugs, medical devices need to be approved by oneEuropean country only, and once registered, become available to all ofEurope.

Monitoring of researchProgress reports are called for at intervals, depending in the

riskiness of the project.The CCPPRB must be provided with all substantial

amendments for approval.In clinical trials, SAEs and other significant findings are

reported to the French Medicines Agency (FMA) within fifteen days ofknowledge of the event, and deaths and life-threatening SAEs reportedimmediately. Those that are not related to the study drug do not needto be reported, but the FMA must be notified immediately by thesponsor if a trial is stopped prematurely. The CCPPRBs do not receivereports of SAEs.

Financial and funding issuesCommercial sponsors are charged a review fee of 9500FF

(approximately A$2500) . Individual, or non-sponsored or officialscientific research institute applications are charged a review fee of900FF (approx. A$250). Fees are standard across all centres. Funds arecollected by the department of health and distributed to participatingCCPPRBs according to their workload.

CCPPRBs decide whether and how much their reviewermembers are to be paid. For example, at Paris-Cochin, members arepaid 500FF (approximately A$125) for whole project reviews, withreviewers of Plain Language Statements paid 100FF (approximatelyA$25) and scientific reports paid 500FF. No member is paid more than10 ,000FF (approximately A$2500) per year for project review. Membersreporting on amendments are paid 100FF. Members who do not writereports are unpaid.

Healthy volunteers can be paid up to 25,000FF (approximatelyA$6 ,250) per year for participating in research.

UNITED KINGDOM

Background and structureImperial College School of Medicine (ICSM) in London was

visited. ICSM is the largest medical school in the United Kingdom, with675 academic members of staff and 2,500 research and support staff.

The author also visited the Oxford Centre for Ethics andCommunication in Health Care (Ethox) , Institute of Health Sciences.Ethox is an academic centre within the University of Oxford's faculty ofclinical medicine. It has close ties with large local hospital trusts, andwith the Oxfordshire Health Authority.


Two types of research ethics committees exist in the UnitedKingdom: Multi-Research Ethics Committees (MRECs), which reviewrnulticentre research at five or more sites, and Local-Research EthicsCommittees (LRECs), which review research at four or fewer sites. Eachresearch ethics committee has its own constitution and terms ofreference (standing orders).

There is one MREC for each region in the United Kingdom, witheight regions in England, one in Scotland and one in Wales. Decisionsof the MRECs are binding for any LREC involved in the whole of theUnited Kingdom. MRECs report to the Secretary of State through theDepartment of Health.

MRECs and LRECs are constituted as follows:• a chair and vice chair, one of whom must be lay• eight to twelve other members, at least one lay• a nurse• a general practitioner• a physician or doctor from the hospital involved.There is no requirement for a lawyer or a minister of religion onresearch ethics committees.

Often lay membership comes from the local Community HealthCouncil, and there must be a balance of sexes and age. As in the othercountries, LRECs are not necessarily linked to, but often exist within,hospitals.


Review is often divided into scientific research and socialscience research, but this varies according to the LREC. Some LRECshave a single application form for their region, but many generate theirown. This may change, however, with the recent establishment of aCentral Office for Research Ethics Committees, set up under theauspices of the Department of Health. This Office may initiate anumber of changes regarding standardisation of forms and review.

Once a multicentre research project is approved by the MREC ,the researcher sends to the LRECs all correspondence associated withthe MREC review, the MREC approval letter, the Plain LanguageStatement and Consent Form and the 'Ann ex D' which containsinformation pertinent to the local site. The LREC has thirty days tocomment. Factors it considers are the suitability of the local site, thesuitability of the local researcher, local Plain Language Statementrequirements and the suitability of the local population. The systemhas not proved to be as efficient as intended. 3 Significant delays inapproval still exist, and some LRECs do not accept the decision of theMREC regarding ethical issues, even though an LREC's brief does notinclude ethical review. The process is under review.

LRECs typically review about two hundred site-specific projectsannually, and about one hundred MREC projects. MREC projects are


generally reviewed by a small LREC sub-committee (about three LRECmembers). LREC projects are typically reviewed in-depth by onemember, who reports to the full committee.

Research initiated by general practitioners must go through anLREC and studies done through general practitioners are reviewed bythe MREC and are generally monitored by Contract ResearchOrganisations,"

Monitoring of researchAnnual progress reports on approved studies are required, and

a final report on completion of the project. In the institutions visited,the MREC or LREC conducts no audits of research projects. SAEs arereported according to the regulatory requirements, but generally LRECreview is very limited. Amendments can be reviewed by the chair andare ratified by the LREC. Every member of the LREC receives a copy ofthe amendments and these can be discussed when the committeemeets.

Financial and funding issuesMRECs charge 1000 pounds (approximately A$2500) to review

external applications, except for National Health Service (NHS) studies,where there is no charge. Payment to LRECs seems to vary, with somecharging 200 pounds per application and others around 800 poundsper application (amendments included), and some do not charge at all.Students are not charged for review of their projects.

Amendments are charged at 200 pounds (approx. A$500) eachby the MREC, and 50 pounds (A$125) each by the LREC. MREC fees goto the NHS, with LRECs funding their own administrative offices.

There are no individual review fees paid to MREC or LRECmembers, but travel expenses can be reimbursed. General practitionerscan have the costs of a locum covered while they are conducting theirresearch reviews.

Research participants are paid according to the guidelines ofthe Royal College of Physicians. Costs can be covered for patients, andhealthy volunteers can be paid quite substantial amounts, but theusual is about five pounds/hour with travel costs covered.

UNITED STATES OF AMERICA

Background and structureThe author visited the University of Pittsburgh Center for

Bioethics and Health Law, University of Pittsburgh Medical Center(UPMC). The Center for Bioethics and Health Law comprises academicsfrom the University of Pittsburgh faculties of history, law, medicine,nursing, philosophy, psychology, and public policy, who have madeextensive contributions through their research, publications, andprofessional service to the field of health law and bioethics.

The Columbia Presbyterian Medical Center (CPMC) was alsovisited. The Columbia centre is formed from an association between the


Columbia University College of Physicians and Surgeons and the NewYork Presbyterian Hospital.

Federal policy regulations require that any institution receivingfederal funding for research must have an assurance agreement withthe Office of Human Research Protection (OHRP) which is a federalgovernment department. Agreements are struck with each institution.It is expected that OHRP regulations apply to all research projects,regardless of whether they are government funded. Before July 2000,the OHRP reported to the National Institutes of Health (NIH), but theOHRP now reports as an individual agency to the Department of Healthand Human Services (DHHS).

Research is reviewed by Institutional Review Boards (lRBs) , whichreport to the OHRP. Federal regulations require IRBs to have at leastfive members diverse in race, sex, cultural background, with memberswhose primary concerns are in scientific and non-scientific areas, andat least one member not associated with the institution.

The University of Pittsburgh Medical Center IRB membershipincludes:• at least one nurse• at least one pharmacist• lay members• lawyers not associated with the institution• at least one minister of religion• at least one physician/researcher.

The Columbia Presbyterian Medical Center IRB membershipincludes:• lay members• at least one clinician• at least one pharmacologist• at least one research scientist• at least one ethicist• an IRB administrator .


Until recently, research was reviewed by research institutecontrolled IRBs, but there are now about seventeen for-profit IRBs inthe United States that review medical research projects. Centralisedreview boards (CRB)5 have been established for multicentre research,and have increased in number, particularly in the 1990s, through theproliferation of multicentre trials and the requirement for ethicsapproval by researchers not affiliated with an institution. The CRBs aretypically located outside institutions, but within corporations, andoperate for-profit and not-for-profit, typically not-for-profit CRBs beingfor specialty research such as cancer.

CRBs are relied upon to approve the ethical and legal aspectsfor multicentre trials. This type of review has been resisted in some


institutions because of perceived legal implications and the loss of localcontrol and authority.

At the two centres visited, IRBs only review projects pertainingto their institutions, and centralised review of multicentre studies isnot established at this stage. IRBs review social science research aswell as clinical trials. The University of Pittsburgh Medical Center(UPMC) and the Columbia Presbyterian Medical Center (CPMC) haveabout 2500 ongoing projects each at anyone time.

The Pittsburgh centre has five IRBs, each with about twentymembers. These IRBs review approximately seventy-five applications amonth, on a rotating basis, with one meeting per week. Projects aremostly a mix of either biomedical or psychosocial research. Projectsare approved within three weeks of submission, with each projectreviewed one week from submission.

For the full IRB at Pittsburgh, there are three primary reviewers:a physician, a pharmacist and a lay member who examines the PlainLanguage Statement for participants. Each provides a brief summary tothe IRB. If the project is not approved at the first sitting of the IRB, theresearchers are asked to attend an interview the following meeting.

Most psychosocial projects are processed expeditiously by thedeputy chair. Low risk biomedical projects are dealt with by the Officemanager or by the IRB chair.

The Columbia centre reviews all projects arising within theinstitution, that are located on site or involve its facilities or facultymembers. With the exception of expedited review, which is done by theIRB chair or designated members, new studies are reviewed by aPrimary Review committee. This committee determines whether the riskbenefit ratio is reasonable, looks at safety aspects of the study,statistics and study design, and whether the Plain Language Statementfully outlines the known and potential risks.

Monitoring of researchMonitoring of research is of particular concern to the federal

government, particularly the validity of the informed consent process,to the extent that and monitoring of consent procedures is nowrequired. In response, the Pittsburgh centre has established a ResearchConduct and Compliance Office, which consists of three staff and hasthree main activities:• random audits: the Office conducts random audits of high risk,

high impact studies. Any problems that arise are sent to theinstitution's Executive for further examination. Most issues are dueto non-compliance with research protocols and ethics approvalconditions. When this happens, the principal researcher can beremoved and the study suspended until the issues are sorted out.

• education of researchers: workshops are held to enhanceknowledge of clinical research processes and regulations.

• quality improvement of the IRB.


Amendments are only expedited if there are no substantial changesto the protocol, or if the risk benefit ratio is not increased, otherwisethe IRB reviews them. An Adverse Event Coordinator reviews andmaintains a database of 8AEs. Only local adverse events that arerelated to the study are reported to the IRE. Progress reports arerequested every twelve months.

At Columbia, the Chair reviews every amendment and every 8AE.Major amendments require the same sort of review as new protocols,and are presented to a Primary Review Committee and the IRE. Adverseevents that are serious and unexpected and at least possibly related toparticipation in the study are reported to the IRB.

Progress reports are due at intervals, depending on the nature of thestudy, the risk involved and the vulnerability of the population.

Financial and funding issuesLike the NHMRC grants, National Institutes of Health (NIH)

grants have no infrastructure costs built in. The NIH directs funding forinfrastructure to the universities, which in turn distribute funds toresearch departments. The NIH pays 70 .5% for infrastructure for everydollar of funding academic centres receive.

At the Pittsburgh centre, the University funds the IRB Office,with no review fees levied on commercially sponsored, or other, studies.The IRB Office currently has a manager, six clerical staff, and threeresearch nurse coordinators whose job it is to maintain good relationswith the researchers. The IRB does not deal with the financial aspectsof research or review contracts or clinical trial agreements. IRBmembers are not paid, except for the chair, who is paid 70% of his/hersalary, for 70% involvement in the IRB's activities. The deputy is paid20% of his/her salary for 20% involvement. Healthy volunteers ofresearch are not paid for risk, but are paid for time and inconvenience.This can be as much as U8$1O-15 per hour.

At Columbia, an infrastructure levy of 25% of project cost ischarged for commercially funded studies to fund staff and otherinfrastructure. The funds collected are reinvested in medical research.It has an Office of Clinical Trials which negotiates the budgets with thesponsors. An IRB review fee of U8$1500 is included in the negotiations.Researchers are allocated some of the funds, as is the IRB office andIRB members. The Office also operates as the research centre andoffers biostatistical advice to researchers. The institution givesresearchers about U8$300 for IRB submission preparation forcommercially sponsored studies.

SUMMARYIn general, the research ethics committees at the four countries

visited were quite similar in terms of membership and basic reviewprocesses. Monitoring methods appear to be more variable. Australia


has a significantly larger number of HRECs per head of population(216) than the other countries (The Netherlands 80, France 48, UK 10).

The main difference between the Dutch and Frenchmembership and those of the UK and USA is the inclusion of anethicist.

Centralised review of multicentre research is established in theEuropean countries visited, and Centralised Review Boards exist in theUnited States. Literature suggests that the UK experience has been lessthan satisfactory. Opinion is that most research ethics committeesprefer to have some participation in the ethics review process.

External HREC members are paid in The Netherlands and inFrance HREC members are paid according to the type of review. In theUK, members are paid for travel. In the USA, the chair and deputychair at UPMC are paid in proportion to the time they spend on HRECactivities.

Volunteers for research are paid for time and inconvenience inall the centres visited. In France there is a limit to how much avolunteer can be paid in any year, but payment is quite substantial.

POINTS FOR CONSIDERATION FOR AUSTRALIAAs mentioned in the introduction, many Australian HRECs are

overworked and monitoring of research is less than optimal. With theincrease in multicentre trials and subsequent workload on HRECs, it isperhaps timely to look at establishing a multicentre review andmonitoring system in Australia.

Multicentre reviewMost multicentre research is research conducted by a single

researcher or sponsor in different institutions or is research conductedjointly by different researchers in different institutions.

Prior to 1991, Commonwealth and State/Territory governmentsreviewed all therapeutic goods (medicines and medical devices) broughtinto, exported from or supplied in Australia. There was full evaluationof all available trial data on safety and efficacy of the therapeutic goods,assessment of the protocol, including ethical considerations, beforesubmission to the HRECs. HRECs of participating institutes were thefinal approval authorities.

This system of review was abandoned in favour of the ClinicalTrial Notification (CTN) and Clinical Trial Exemption (CTX) schemes,implemented in February 19916 • Under the CTN scheme, individualHRECs performed their own reviews of the safety and efficacy oftherapeutic goods to be trialled in their institutions. Under CTX, theTherapeutic Goods Administration (TGA) performed the review, withfinal approval given by the participating HRECs. It was anticipated, atthe time, that most applications submitted would go by the CTX route.However, it has proved to be otherwise, with almost all but very earlyphase studies being reviewed under CTN, most likely because it isfaster and cheaper to obtain approval.


The result of localised review of therapeutic goods is thatstandards of application and review vary from site to site; insurance,indemnity and other financial arrangements differ, and vast resourcesare used in terms of preparation and distribution of ethics applications,review time and paper. In addition, approval times vary, which addspressure on researchers of late approvals to reach recruitment targetsquickly - the ethical implications of this are obvious.

The National Statement encourages prompt and efficient reviewof multicentre research, and promotes the idea of single review by aninstitute or group which will be accepted by the participatinginstitutions or researchers.

As a starting point, based on practices observed overseas, theauthor presents the following method of review, a MultiCentre Review(MCRI, for consideration:• Each state, or combination of states, becomes a 'region', perhaps

with Western Australia, Northern Territory and Queensland beingone region, the ACT combining with New South Wales, andTasmania and South Australia combining with Victoria

• Projects to be conducted at three or more sites per region areeligible for MCR

• A 'principal' site is chosen for the review. This could be theinstitution specialising in the illness being studied, or a site chosenby the participating institutions or a commercial sponsor.

• Applications are presented to the HREC of the principal site, the'Principal Research Ethics Committee' (PREq on a standardapplication form?

• The suitability of the site is established• PREC membership consists of a chair (this could be the chair of the

principal site HREq who coopts HREC members from each of theparticipating sites to form the PREC. These members should havean understanding of the local community and institutional valuesand requirements. Membership should include those with expertisein the areas of disease or illness under enquiry. The resultingcommittee is to conform to the guidelines of the NationalStatement. Coopted members may nominate an alternate orsubstitute if necessary.

• A coordinator is employed to present the submission to the PRECand coordinate activities between sites, such as indemnities,Clinical Trial Agreements, insurance, liaison with the insurers andongoing administrative activites. Funding should be provided forthe coordinator, either through sponsor contributions or thegovernment.

• The principal researcher from each participating site may be askedto attend the PREC meeting

• After PREC review, the complete application with all relevantdocumentation from the PREC deliberations is provided to the chairor secretary of each HREC involved


• Coopted members report the recommendations of the PREC to theirown HREC, or a subcommittee thereof, for local approval

• Any issues arising at a local level are conveyed by the cooptedHREC member to the coordinator or the PREC chair for resolutionin a timely manner

• Certain site-specific details, such as location, contact personnel,need to be included in the Plain Language Statements

• Both PRECs and HRECs should adhere to strict approval deadlines• The coordinator liaises with participating HREC

secretariats/researchers, distributes serious adverse eventsummaries and other safety data, new Investigator Brochures,coordinates review of protocol amendments, and other informationreleased by individual institutions, sponsors or regulatoryauthorities.If centralised review of multicentre research is to achieve its aims,

the following pitfalls should be avoided:• Lack of communication between the PREC and participating

HRECs, hence the involvement of a coordinator and a local HRECmember on the PREC.

• Projects should be reviewed and approved within a reasonable time,eg 5 weeks

• Redundant review. The PREC should be composed of members whohave the expertise to review the applications to a high standard,and their recommendations should be accepted by the local HRECswithout further review. The inclusion of a representative from eachHREC should satisfy local HRECs that their viewpoints are beingpresented to the PREC.

In summary, possible points in favour of multicentre review are:• consistency of standard of review• consistency of insurance cover• consistency of indemnity• consistency of wording in Clinical Trial Agreements• reduction in review time spent by local HRECs• consistency in approval/ starting times

Possible points in opposition to multicentre review:• longer turnaround time if individual HRECs insist on local review• continuing differences in requirements for wording of Plain

Language Statements• disagreement over central review committee decisions• reduced acknowledgement of local community values and

requirements• reduced reviewer 'pool ', ie fewer opinions expressed in discussion,

therefore there is a chance that important ethical or scientificissues will be missed

Monash Bioeth ics Review Vol. 20 No.2 75 Ethics Committee Supplement

Monitoring of researchOngoing review of research remains less than ideal and leaves

research participants, researchers, hospitals and other institutionsexposed to risk following ethics approval. It is suggested that, atapproval time, projects be given a risk rating, which corresponds to aprogress report interval and/or an audit interval, i.e. very high riskprojects have a 10 'ri sk rating, and very low risk projects have a 1 riskrating. Researchers conducting research with a high risk rating couldbe asked to submit, say, quarterly progress reports, or an auditconducted after a predetermined time. Low risk rated projects could berequired to submit progress reports at longer intervals, say annually.

A more secure system for review of serious adverse events(SAEs) in multicentre research could be considered. The current systeminvolves the reporting of all SAEs to all researchers and HRECsinvolved. These reports are often difficult to evaluate, and researchersare left with this responsibility. A suggestion is for a centralised reviewcommittee (like the PREC) to review all adverse events and provide acomprehensible reporting system to researchers and HRECs.

As an extra measure, it is suggested that an independent auditcommittee be set up to review projects in progress. The committeeshould include a person from outside the institution, possibly a retiredresearcher, and one or two HREC members familiar with the project.The committee should be funded by the institution and would conductaudits according to the risk rating intervals.

Financial and funding issuesWhere research costs have a significant impact on an

institution's finances, it is suggested that a model such as theColumbia Presbyterian Medical Center Office of Clinical Trials beconsidered to centralise the research finances, including preparation ofbudgets.

Consideration could also be given to:• standardisation of HREC review and infrastructure fees• standardised payment to HREC members on a fee for service basis• standardised payment to healthy research volunteers.

Education and trainingNew HREC members generally need education in understanding

the requirements of the National Statement and how to review researchproject applications. It is suggested that workshops be conducted atintervals throughout the year. Members would be educated in basicethical principles, given help in interpreting the ethics application form,the Plain Language Statement and the consent process, medical andscientific terms in the protocol, regulatory requirements and learningbasic research design techniques.


To maintain high standards of research conduct, it is suggestedthat all researchers take part in education in good clinical researchpractice.

CONCLUSIONThe first hand information the author received indicated that

standards of review in Australia are at least equivalent to thoseoverseas in terms of membership, review and monitoring. Although thecentralised review process for multicentre trials has its problems, theseproblems are not ones that cannot be resolved, and if a system isadopted in Australia, it may well reduce effort, paperwork, time, andraise review standards for those HRECs that cannot provide thenecessary expertise and whose infrastructure is not well supported.Standardisation of review fees would provide a more consistentapproach to the funding of HREC secretariats, and avoid potential'playing off by commercial sponsors. Education of HREC members isan integral part of lifting and maintaining review standards andconsideration to education and training programs would serve us well.Time and effort would also be saved if regular training programs wereestablished for researchers to maintain standards of good clinicalpractice.

END NOTES

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CCMO website:www.ccmo.nlThe 'ethicist' is a person with at least five years' exp erience in dealing with ethicalissues.Multicentre research ethics: has the cure been worse than the disease? EditorialsBMJ 2000;320:1157-1158 (29 April) Responses of local research ethics committeesto a study with approval from a multicentre research ethics committee, Andrew LLux, Stewart W Edwards, John P Osborne, BMJ 2000;320:1182-1183 (29 April)The new system of review by multicentre research ethics committees: prospectivestudy, Joanna Tully, Nelly Ninis, Robert Booy, Russell Viner BMJ 2000;320:11791182 (29 April)Contract Research Organisations are generally for-profit companies set up tooversee and monitor research projects, usually for commercial drug companies.Demystifying Central Review Boards: Current Options and Future Directions,"22,no.6, IRB Dec. 2000 ppl,8.Therapeutic Goods Act 1989A common application form is being developed by the University of New SouthWales and the Victorian Department of Human Services and a number of VictorianHRECs are currently using a pilot version .The common application form has a sample Plain Language Statement. Use of thiswould ensure some consistency.

I would like to thank all the people overseas who set aside time to discusstheir ethics processes with me. These include Albert Vermaas, CarolineBouma, Liesbeth Meijer, Ruud ter Muelen, Muriel Echemann, ChristopheGrenot, Georges Hazebroucq, Richard Ashcroft, Michael Parker, Tony Hope,Mark Wicclair, Michael DeVita, Denis Swanson, Alan Meisel, Donald Kornfeld,Michael Leahey, Evan De Renzo, Chris McKee.

Monash Bioethics Review Vol. 20 No.2 77 Ethics Comm ittee Supplement

I would also like to express my appreciation to The Alfred hospital for itsgenerosity in funding the trip.

FURTHER REFERENCES1. Fundamentals of Human Subject Research Clinical Research Workshop, 22 June

2000, Sponsored by Universi ty of Pittsburgh2. stet.3. UPMC Phys ician, July 2000, Vol. 9 , No.7, UPMC Health System4. OPRR Reports Protection of Human Subjects Title 45 Code of Federal Regulations

Part 46, Revised June 1991, Reprinted April 2 19965. Human Research Report Protecting Researchers and Research Subjects Volum e IS,

No.6 , June 20006 . French Medicines Agency Guideline for Reporting of Serious Events and New

Information during Clinical Trials conducted on Medicines, Translated and ad aptedfrom the French original version published on November 15th 1994

7 . Agence Francaise de Securite Sanitare des Produits de Sante Declarationd'intention pour toute investigation clinique portant sur des dispositifs medicauxGuide Practique 10i du 20 Decembre 1988 Modifiee sur la Protection des Personnesqui se pretant aux Recherches Biomedicales, 1997 Doin Editeurs/AssistancePublique-Hopitaux de Paris

8. Medical and ethical review of drug research in the Netherlands: report of a studyconducted by the Institute for Bioethics, Maastricht, Ron P Berghams, Ruud HJ terMeulen and Maurice AM De Wachter, International Journal of PharmaceuticalMedicine 1997, 11:167-170

9. 'Unresponsive' NHS ranked 18th in world, Jeremy Lau rance and Cherry Norton, 21June 2000, The Independent

10. World Medical Association Declaration of Hels inki, Adopted by the 18th WorldMedical Assembly, Hels inki, Finland, .Jurie 1964 and amended in Tokyo 1975, inVenice 1983, in Hong Kong 1989 and in South Africa, October 1996

11. Guideline for Good Clin ical Practice ICH Harmonised Tripartite Guideline (EMEAStatus as of June 1996)

12 . CCMO website: www.ccmo.nl13. ETHOX website: www.ethox.org.uk

Documents

Research ethics committees: what can we learn from the Western European and United States experience?