Module 2.1 Training and Resources in Research Ethics ...

Module 2.1

Training and Resourcesin Research Ethics Evaluation

© TRREE, 2009-2018 http://elearning.trree.org/1

Part 2. Research and ethics evaluation

© TRREE, 2009-2018 17 http://elearning.trree.org/2

2.1. What research requires ethics evaluation

Generally speaking, all research that involves humans must be evaluated and approved by acompetent REC before the research begins or, more precisely, before any prospective participantsare contacted for recruitment. This is often referred to as the ethics review requirement. The ethicsreview requirement also applies to research conducted with personal information found forexample in medical files, or with human tissue and products such as genetic material. Researchwith gametes, embryos and fetal tissue also requires prior ethics review in addition to a number ofother requirements.

The ethics review requirement is found in many international guidelines and in many nationalregulations and/or guidelines and it applies to all types of research involving humans.

The ethics review requirement is triggered when an activity constitutes research and will involvehumans. Research is a term that is difficult to define and there are many grey zones. Generallyspeaking “research” aims at developing generalizable knowledge. It can be conducted by differenttypes of researchers, in many different fields of inquiry (health, social sciences, humanities, etc.)and using different methodologies (clinical trials, record review, observation, participation, andother qualitative approaches).

In some countries, certain types of research may be exempted from the REC review requirementunder certain conditions. The REC will assess if a project qualifies for one of the exemptions. Aresearcher cannot issue his/her own exemption for a study. An exemption must be issued by anREC.

WMA, Declaration of Helsinki, 2013, Para. 1, 23.ICH-GCP, 1996, Sec. 2.6.CIOMS, International Ethical Guidelines for Biomedical Research Involving HumanSubjects, 2002, Guideline 2.COUNCIL OF EUROPE, Convention on Human Rights and Biomedicine, 1997, Art. 16(iii).COUNCIL OF EUROPE, Additional Protocol to the Convention on Human Rights andBiomedicine, concerning Biomedical Research, 2005, Art. 2, 7, 9(1).EU Directive 2001/20/EC on Clinical Trials, Art. 2(a), 6(2), 9(1).US 45 CFR 46 Protection of Human Subjects - Common Rule, 2009, Art. 46.101, 46.102.


2.2. Particular cases

Some kinds of research require, in addition to ethics evaluation, other reviews and approvals. Inaddition, some kinds of activities may well resemble research but do not constitute researchinvolving humans and thus do not require evaluation and approval by a REC. This section providesexamples of these two types of activities.

Clinical trials are a good example of a type of research that has additional requirements. In manycountries, sponsors of drug trials must ask the competent government authority (or regulatorybody) for authorization to use an experimental drug in a trial. Investigators are legally required tohave both the government approval for use of an experimental drug and REC approval before atrial can start. In other countries, there is a system of notification of all drug trials to the nationaldrug agency.

In countries where it is not forbidden to undertake research involving human reproductive material(stem cells, gametes, embryos), there will often be a requirement that national oversightcommittees review the research project in addition to the competent REC.

Other types of research that may need additional approvals are studies involving school children.In some countries, in order to engage school children in research, a proposal may need to beapproved by relevant Government authorities such as the Ministry of Education at the nationallevel and other authorities at the regional, district and schools levels.

The important point here is that whatever the additional requirement, it does not replace ethicsevaluation and approval by the competent REC. Nor should a positive approval from the otherauthority influence the conduct of ethics evaluation. Both reviews are necessary.

Some activities may be conducted for purposes such as quality assurance, education or research.Chart reviews are one such activity. For example, a person may wish to have access to medicalcharts to assess the quality of a certain type of procedure. When conducted for quality assurancepurposes only, chart reviews do not require REC approval, although other types of approval maybe necessary. When it is not clear whether or not an activity requires ethics committee approval,the Chair of the REC should be consulted.


2.3. What aspects get evaluated and why

Ethics evaluation of research projects generally aims at ensuring that projects are – or can bemodified to become - ethically acceptable. Among other criteria, RECs will ensure that projectsoffer a favourable risk-benefit ratio and are consent-worthy for prospective participants. Thisrequires that the science and ethics of projects be evaluated and found acceptable.

2.3.1. Scientific aspects

All protocols involving human participants should undergo an independent and rigorous scientificreview to assess the scientific quality, the potential of the research to increase knowledge, theappropriateness of the study methodology to answer a precisely articulated scientific question, thequalifications of the applicants to conduct the research, and in some cases, clinical questions. Forexample, the design of clinical trials should be based on sound statistical principles andmethodologies, including sample size, use of controls, randomization, population stratification,stopping rules, and the feasibility of relating endpoints to objectives. Ensuring that the chosenstudy design minimizes bias and generates data that will answer the scientific question requiressome understanding of the research process and the topic to be studied. These issues are pivotalto a successful study and must be evaluated before considering the ethical aspects of theproposed study.

The scientific evaluation can be conducted by the REC if it has membership with appropriatescientific expertise. Otherwise, a separate scientific review committee should conduct the scientificreview, the results of which can then be communicated to the REC. It should be noted that theapproval provided by government authorities to authorize the use of an experimental drug in a trialis not considered an appropriate scientific review. Even if the REC does not conduct the scientificevaluation, it can always consider scientific issues as they relate to the ethical acceptability of theproject (see below 3.3)

There will always be some level of overlap between scientific and ethical review, most notably onthe issue of the importance of the research question (see below 3.2 & 3.3)

2.3.2. Ethical aspects

Once a project has received a favourable scientific review, the REC will then evaluate its ethicalacceptability. The ethics evaluation involves examining the scientific and financial as well as theethical aspects of a project. There are several ways of breaking down the scope of ethicsevaluation. Generally, the REC must conduct the ethics evaluation of projects according to thefollowing criteria:

Community participation or collaborative partnershipSocial value: relevance of research to local health needs & expectationsScientific validityQualifications of investigatorsParticipant selection processAcceptable balance of risks and potential benefitsInformed consentPrivacy and confidentialityFair compensation/reimbursementConflicts of interestScientific integrityOngoing respect for research participants and collaborating communities


These are discussed in more detail below (part 3).

It is particularly important to note that a project that is not scientifically sound is not ethicallyacceptable because it will expose participants to the risks and potential harms of research withouthaving the possibility of yielding benefits to the participants and/or to society. Thus, the REC mustensure that appropriate scientific evaluation has occurred even if it does not conduct the scientificassessment itself. If a project does not pass scientific evaluation, then it should be denied ethicsapproval as well.

2.3.3. Financial aspects

Another important aspect of ethics evaluation is the assessment of the financial components ofprojects. This requires that the REC ensure that the investigator is free of conflicts of interests orthat these are properly managed, and that prospective participants will not be unduly influenced toparticipate.

Emanuel E.J., Lemmens T., Elliot C., 2006


2.4. Levels of evaluation

It is generally accepted that RECs can adopt a proportionate approach to ethical evaluation: thegreater the risks of a project, the greater the scrutiny. In practice this means that RECs can usetwo approaches to ethics evaluation:

Evaluation by the full committeeEvaluation by a sub-committee which is also called “expedited review”

Projects that pose only minimal risk can undergo expedited review, if the REC operatingprocedures so provide. Projects that pose greater risks deserve attention by the full REC to ensureproper safeguards are in place.

Full committee evaluation will involve all members’ comments and discussion of all ethical issuesarising from the proposed study and the deliberations thereof and reaching a consensus on anREC decision. This will take place in an ordinary REC meeting, scheduled according to thestandard operating procedures.

RECs should establish procedures for expedited review of research proposals. These proceduresshould specify the following:

1. The nature of the applications, amendments and other considerations that will be eligiblefor expedited review

2. The quorum requirements for expedited review3. The status of decisions (that is, whether or not subject to confirmation by the full REC)

In some countries national regulations establish categories of research that pose no more thanminimal risk that can receive expedited review.

WMA, Declaration of Helsinki, 2013, Para. 17.WHO, Operational Guidelines for Ethics Committees, 2000, Sec. 6.3.US 45 CFR 46 Protection of Human Subjects - Common Rule, 2009, Art. 46.110.


2.5. Ethics review of international collaborative research

International collaborative research, sometimes referred to as externally sponsored researchrequires two ethics evaluations:

One in the country of the sponsor of the research (usually from the investigator’sorganization), andOne in the host country (i.e. where the trial will be conducted and participants recruited)

In these situations, both approvals must be obtained before the research can start. Both RECs willconduct a full review of the project.

The REC in the sponsoring country must ensure that the research meets its own national as wellas international ethical standards.

The REC in the host country has a special responsibility to determine whether the objectives of theresearch are responsive to the health needs and priorities of that country. The ability to judge theethical acceptability of various aspects of a research proposal requires a thorough understandingof a community's customs and traditions. The REC in the host country, therefore, must have aseither members or consultants persons with such understanding; it will then be in a position todetermine the acceptability of the proposed means of obtaining informed consent and otherwiserespecting the rights of prospective participants as well as the means proposed to protect thewelfare of the research participants. Such persons should be able, for example, to indicate suitablemembers of the community to serve as intermediaries between investigators and participants andto advise on whether material benefits or inducements may be regarded as appropriate in the lightof a community's gift-exchange and other customs and traditions.

The European Union explicitly requires that all clinical trials that are to be taken into account formarket authorization be conducted in accordance with the principles of the Declaration of Helsinkiwhether they are conducted in the EU or elsewhere.

WMA, Declaration of Helsinki, 2013, Para. 10, 23.ICH-GCP, 1996, Sec. 2.1.CIOMS, International Ethical Guidelines for Biomedical Research Involving HumanSubjects, 2002, Guideline 3.COUNCIL OF EUROPE, Additional Protocol to the Convention on Human Rights andBiomedicine, concerning Biomedical Research, 2005, Art. 9.1, 29.EU Directive 2001/20/EC on Clinical Trials, 2001, Art. 7.US 45 CFR 46 Protection of Human Subjects - Common Rule, 2009, Art. 46.114.


Part 3. Ethics evaluation of research projects

This part discusses core issues that ethics committees need to address when conducting ethicsreview of research projects. For this purpose, questions that need to be addressed when reviewingprojects are identified. Before providing ethics approval of a project , the REC must be satisfiedthat the issues raised by these questions have been properly addressed.


3.1. Community participation or collaborative partnership

Community participation, or collaborative partnerships, refers to several elements that should bepart of the research process to avoid, or at least minimize, the possibility of exploitation.

“A exploits B when B receives an unfair level of benefits or unfair burden of risks as a result ofinteracting with A.”(Emanuel et al, 2004)

Research in developing countries has a greater potential for exploitation of local participants thanresearch in developed countries. For example, local communities who participate in, and bear therisks and burdens of, research designed to be conducted in developing countries would beconsidered as having been exploited if the benefits accrue mostly to people in developedcountries.

Does the proposed project involve a collaborative partnership?

Ethics guidelines as well as the ethics literature agree that community participation is key todiminishing the risks of exploitation.

Of direct interest to RECs, this involves:

Ensuring that the research is responsive to the health needs of the community to beinvolved. This means that the importance of a problem and the setting of priorities forresearch will be determined in partnership with local communities.Ensuring that successful interventions are reasonably made available to the community.This requires the sponsor of the research to initiate a negotiation with stakeholders in thehost country, representatives of the communities from which participants are drawn andnon-governmental organizations such as health advocacy groups to determine the practicalimplications of making the products of research available to the local community.Developing local capacities.Ensuring that the participants and communities receive benefits.

Ezekiel E.J., Wendler D., Killen J., Grady C., 2004.

WMA, Declaration of Helsinki, 2013, Para. 22, 20, 34.WHO, Operational Guidelines for Ethics Committees, 2000, Sec. 6.2.6.CIOMS, International Ethical Guidelines for Biomedical Research Involving HumanSubjects, 2002, Guidelines 3, 10, 20, 21.


3.2. Social value: relevance of research to local health needs &expectations

In order for research involving humans to be ethical, it must have social value. Demonstrating thesocial value of a proposed project is a critical component of the REC review process. Concretelythis means that in order to justify including humans in research, researchers must convince theREC of the importance of the research objective(s) for society.

Without demonstration of this element, a REC will have no choice but to suspend its review orreject the project.

Does this project have social value?

Generally, research will be considered as having social value when the hypotheses or questionsbeing researched will have potential benefits for the individuals and/or community where theresearch takes place. This value may accrue to individuals, to advancing knowledge in relation toan important topic or issue for that society, or to some combination of these benefits.

Another example of social value, or lack thereof, involves phase 4 clinical trials. These trials occuronce a drug is marketed. In many cases, they will aim to increase safety data about a drug.However, in some cases when drugs are already well documented, the objectives of such trialshave little or no social value since they are no more than marketing initiatives, aiming to getpatients to take a given drug rather than another. In this latter situation, the study may lack socialvalue and the REC should refuse it.

In the context of international collaborative research agreements, or of externally sponsoredresearch, RECs must be particularly careful to ensure that the proposed project is relevant to localhealth needs and addresses issues that are perceived by the community as needing to beaddressed. In other words, the prospective research community should consider the questionbeing addressed as a problem that deserves to be investigated. For example, the knowledgegenerated could contribute to diminishing the morbidity or the mortality of certain patients or toimproving the quality of life of the local population by solutions that are reasonably made availableto local communities and are socio-culturally acceptable.

What is the social value of student research?

Student research does not always generate new knowledge or original work. Rather, the value ofstudent research consists in their education and training on how to conduct research involvinghumans. Although student research mainly benefits the students themselves, it can be consideredto benefit society indirectly because the students may eventually become fully qualifiedresearchers who can undertake research on issues of direct relevance to their community.


3.3. Scientific validity

In addition to having social value, in order for a research project involving humans to be ethical, itmust be scientifically valid. Research that is deemed to lack scientific validity is consideredunethical since such research would not allow for meaningful conclusions, while unnecessarilyexposing participants to risks of inconvenience, or even of harm. This contravenes the overarchingprinciple of respect for persons and human dignity and wastes society’s resources.

Is the proposed project scientifically valid?

Scientific validity is attained when research has the potential to result in facts, reproducibleobservations, or generalizable information in relation to the question under study. In other words,the project proposes a sound methodology and protocol design that is likely to lead to reliableconclusions and is adequate to answer the research question(s). (See also Section 2.3.1)(Freedman, 1987)

A scientific committee, a sub-committee of the REC, or the REC itself, can perform the scientificevaluation. Regardless of who performs the evaluation, ultimately the responsibility to ensure thatan appropriate scientific evaluation is performed on all research projects involving humans is thatof the REC. Even if a scientific committee reviews and provides approval of a given project, RECscan raise questions about the scientific aspects of the project and ultimately have the final say onthe project’s approval.

During a scientific review, the REC may review or request to review any information anddocumentation that is judged as relevant for a proper evaluation. This might include but is notlimited to the following:

a. Name and qualifications of the researcher(s): in order to evaluate whether theresearcher(s) is competent and qualified to conduct the research.

b. Objectives and/or hypothesis: determine whether they are clear, well-designed, andreasonably attainable.

c. Comprehensive literature review: to outline the knowledge available in the discipline’sscientific literature and demonstrate how the project will add to this knowledge. Based onthis information, the REC determines whether the project has sufficient scientific merit.

d. Results of the pre-clinical laboratory and animal studies (when applicable): providesimportant information for the REC on potential benefits and risks.

e. Justification for the use of human participants: the reason for the research, how theresearch contributes to the advancement of knowledge and/or the well-being of humans,scientific assessment of risks for participants

f. Method: to evaluate whether the study is designed in such a way that it could lead to validand meaningful scientific conclusions, applicable and pertinent to the discipline and at thesame time is designed to minimize risks and maximize the potential benefits.

Freedman B., Scientific value and validity as requirements for research: a proposedexplication, 1987.

WMA, Declaration of Helsinki, 2013, Para. 21, 22.WHO, Operational Guidelines for Ethics Committees, 2000, Sec. 6.2.1.ICH-GCP, 1996, Sec. 2.5.CIOMS, International Ethical Guidelines for Biomedical Research Involving HumanSubjects, 2002, Guidelines 1, 2.


COUNCIL OF EUROPE, Convention on Human Rights and Biomedicine, 1997, Art. 16(iii).COUNCIL OF EUROPE, Additional Protocol to the Convention on Human Rights andBiomedicine, concerning Biomedical Research, 2005, Art. 7, 8.EU Directive 2001/20/EC on Clinical Trials, 2001, Art. 6(3).


3.4. Qualifications of researchers

Is the researcher qualified?

Research should only be conducted by qualified researchers or under their supervision. This iscritical for two reasons: to ensure the safety of participants and to ensure that the project will beconducted appropriately and lead to results. Researchers, whether or not they are from licensedprofessions, should demonstrate they have competence acquired through appropriate education,training and experience to conduct the proposed project.

In addition, when reviewing clinical trials, RECs should ask for relevant documents and medicallicenses from investigators to ensure regulatory requirements are met.

WMA, Declaration of Helsinki, 2013, Para. 12.ICH-GCP, 1996, Sec. 2.8, 3.1.2, 4.1.WHO, Operational Guidelines for Ethics Committees, 2000, Sec. 6.2, 3.1.CIOMS, International Ethical Guidelines for Biomedical Research Involving HumanSubjects, 2002, Guideline 1.COUNCIL OF EUROPE, Additional Protocol to the Convention on Human Rights andBiomedicine, concerning Biomedical Research, 2005, Art. 8, 21(2).EU Directive 2001/20/EC on Clinical Trials, 2001, Art. 2(f), 2(k), 3(3), 6(3)d).


3.5. Participant selection process

3.5.1. Is the proposed participant selection process fair?

The fair distribution of the anticipated risks and potential benefits of participating in research is aconcrete way of applying the principle of justice in research ethics.

The selection of research participants must be fair. When reviewing the choice of the studypopulation and inclusion and exclusion criteria for research participants, RECs should ensure thatthe choice of the study population is based on scientific considerations, minimizes risk, andinvolves the participation of the targeted community. They should also try to ensure that theindividuals and communities who share in the risks of the research participation also share in thebenefits, and vice-versa.

3.5.2. How does a REC ensure proper consideration when populations in situations ofvulnerability are proposed as study populations?

Populations in situations of vulnerability include persons incapable of consenting to researchparticipation (e.g., children, incapable adults), persons unduly susceptible to harm (e.g. migrantpopulations, the homeless, sex trade workers and drug abusers), and persons in situations wherea voluntary consent is questionable (e.g., prisoners, soldiers, patients who do not have access tohealth care and students who are invited to take part in the research project conducted by theirsupervisor). RECs must ensure special protections for such populations.For example, people who are not legally competent to consent to research participation must onlybe involved in research projects that require using people from those groups to answer theresearch question. In addition, they or members of their group must potentially benefit from theresearch, and their legal representatives must authorize their participation in the research.

WMA, Declaration of Helsinki, 2013, Para. 5, 7, 28, 30.ICH-GCP, 1996, Sec. 4.8.13, 6.5.WHO, Operational Guidelines for Ethics Committees, 2000, Sec. 6.2.2.CIOMS, International Ethical Guidelines for Biomedical Research Involving HumanSubjects, 2002, Guidelines 9, 12-17.COUNCIL OF EUROPE, Convention on Human Rights and Biomedicine, 1997, Art. 17.COUNCIL OF EUROPE, Additional Protocol to the Convention on Human Rights andBiomedicine, concerning Biomedical Research, 2005, Art. 15, 18-20.EU Directive 2001/20/EC on Clinical Trials, 2001, Art. 4(e), 5(e).US 45 CFR 46 Protection of Human Subjects - Common Rule, 2009, art. 46.111 (a) (3),46.204-205, 46.305-306, 46.404-409.


3.6. Acceptable balance of risks and potential benefits

Principles of doing good (i.e., beneficence) and of not doing harm (i.e., non-maleficence) cometogether in research ethics in an effort to bring about more good than harm in the researchprocess. In doing this, researchers should try to optimize the potential benefits and minimize risksfor participants and others affected by the research.

What are the potential benefits of a project?

Potential benefits can take a number of forms and involve a number of people. There can bephysical benefits (e.g., better health), psychological benefits (e.g., satisfaction of participating in thedevelopment of knowledge), social benefits (e.g., new drug formulation, a cheaper drug, newscientific knowledge), and economic benefits (e.g., free access to drugs or profits). Researchers,institutions, sponsors, research participants and society as a whole can share in these benefits,either directly or indirectly.

Benefits can be further classified as:

Direct benefits to participants when the research procedures have the potential ofbenefiting them. For example, a study offering a new treatment of hypertension offers thepossibility of a direct benefit of treating the hypertension.Indirect benefits to participants when benefits result to them from aspects other than theresearch procedures themselves. For example, if as part of a drug trial participants get afull medical check-up, they may have health-benefits as a result of the check-up (indirectbenefits) rather than from the experimental drug.Benefits to society such as the prospect of a healthier population, a better trained healthworkforce or infrastructure improvements (e.g., a new community clinic).

What are the risks raised by a project?

A risk is the potential for an adverse outcome (harm) to occur. Harms associated with a researchproject can take a number of forms and affect a number of people. There can be physical (e.g.,injury, illness, disability, side effects), psychological (e.g., anxiety, emotional distress, reactivationof trauma, embarrassment), social (e.g., stigma, breach of confidentiality) or economic (e.g., loss ofincome due to time away from work).

Most research risks will be direct risks to research participants. In some cases, there may also bepotential harms to “third-parties” such as to the unborn fetus or to communities.

RECs need to identify all risks of research.

What is the probability and gravity of the risks and potential benefits?

Risks and potential benefits vary in probability and gravity. For example, the risks in a givenresearch project might include a high probability for a minor harm (e.g., small bruise at an injectionsite), a low probability for a serious harm (e.g., disability, death), and/or risks with some othercombination of probability and gravity.

Similarly, potential benefits may be highly probable but rather minor (e.g., satisfaction from sharingone’s opinion about something one cares about), highly unlikely but quite significant (e.g., controlof HIV infection), something in between the two, or there may be no benefit at all.


How are risks and benefits assessed?

RECs need to clarify who bears research risks and to whom potential benefits will accrue. To beacceptable, the research risks to participants must be considered reasonable in relation to thepotential direct and indirect benefits to participants. This requires careful consideration andjudgment by the REC. This process is often called the balancing of risks and potential benefits.(see next section).


3.6. Acceptable balance of risks and potential benefits (continued)

The centrality of risk-benefit evaluations

A critical part of the work of RECs involves the balancing or evaluating of the risks and potentialbenefits of a project. In effect, the REC strives to ensure that no potential research participant –sick or well, young or old – is offered participation in research that is an unreasonable choice andunworthy of consent.

Declaration of Helsinki, Paragraph 18:“Every medical research study involving human subjects must be preceded by careful assessmentof predictable risks and burdens to the individuals and communities involved in the research incomparison with foreseeable benefits to them and to other individuals or communities affected bythe condition under investigation.”

What is an acceptable balance of risks to benefits?

Requirements for acceptable balance of risks to potential benefit are addressed in various ways inregulation and guidelines. National regulations may establish thresholds of risk to benefitassessments that must be respected locally for certain types of populations. Guidance provided byleading instruments can be summarized as follows:

Declaration of Helsinki 2008

In medical research involving human subjects, the well-being of the individual researchsubject must take precedence over all other interests (paragraph 6).Medical research involving a disadvantaged or vulnerable population or community is onlyjustified if the research is responsive to the health needs and priorities of this population orcommunity and if there is a reasonable likelihood that this population or community standsto benefit from the results of the research (paragraph 17).

CIOMS

The potential benefits and risks are reasonably balanced and risks are minimizedRisks of 'beneficial' interventions or procedures must be justified in relation to expectedbenefits to the individual subjectRisks of interventions without the prospect of direct benefits to subjects must be reasonablein relation to the importance of the knowledge to be gained (benefit to society)

Despite this guidance, RECs around the world struggle with this issue. There are no categoricalanswers, thus the importance of the work of RECs. It is generally considered that there is anasymmetry between who bears risks and who bears the benefits: on the whole it is the researchparticipant who bears the burden of research risks while the benefits usually accrue to society aswell as to researchers.

Declaration of Helsinki (2008)

Paragraph 21. “Medical research involving human subjects may only be conducted if theimportance of the objective outweighs the inherent risks and burdens to the research subjects.”

Paragraph 27: “For a potential research subject who is incompetent, the physician must seek


informed consent from the legally authorized representatives. These individuals must not beincluded in a research study that has no likelihood of benefit for them unless it is intended topromote the health of the population represented by the potential subject, the research cannotinstead be performed with competent persons, and the research entails only minimal risk andminimal burden.”

Paragraph 32. “The benefits, risks, burdens and effectiveness of a new intervention must betested against those of the best current proven intervention except in the following circumstances:

The use of placebo, or no treatment, is acceptable in studies where no current provenintervention exists; orWhere for compelling and scientifically sound methodological reasons the use of placebo isnecessary to determine the efficacy or safety of an intervention and the patients whoreceive placebo or no treatment will not be subject to any risk of serious or irreversibleharm. Extreme care must be taken to avoid abuse of this option.

CIOMS, International Ethical Guidelines for Biomedical Research Involving Human Subjects

GL8. Benefits and risks of study participation“For all biomedical research involving human subjects, the investigator must ensure that potentialbenefits and risks are reasonably balanced and risks are minimized.

Interventions or procedures that hold out the prospect of direct diagnostic, therapeutic orpreventive benefit for the individual subject must be justified by the expectation that theywill be at least as advantageous to the individual subject, in the light of foreseeable risksand benefits, as any available alternative. Risks of such 'beneficial' interventions orprocedures must be justified in relation to expected benefits to the individual subject.Risks of interventions that do not hold out the prospect of direct diagnostic, therapeutic orpreventive benefit for the individual must be justified in relation to the expected benefits tosociety (generalizable knowledge). The risks presented by such interventions must bereasonable in relation to the importance of the knowledge to be gained.”

GL9. Special limitations on risk when research involves individuals who are not capable of givinginformed consent“When there is ethical and scientific justification to conduct research with individuals incapable ofgiving informed consent, the risk from research interventions that do not hold out the prospect ofdirect benefit for the individual subject should be no more likely and not greater than the riskattached to routine medical or psychological examination of such persons. Slight or minorincreases above such risk [minimal risk] may be permitted when there is an overriding scientific ormedical rationale for such increases and when an ethical review committee has approved them.”

Are the risks of the project reasonable in relation to the potential benefits?

Generally, a project will be considered acceptable if, in the judgment of the REC, the risks arereasonable in relation to the benefits. In conducting this risk to benefit assessment for specificprojects, RECs repeatedly stumble on questions like what kinds of risks must be considered and towhom benefits should accrue. As well, the notion of “reasonable” is quite vague. This evaluationinvolves a complex judgment call that brings together various concepts.

A method for systematically assessing risks, called component analysis, has been developed toassist in this evaluation and to promote a more consistent evaluation by, and amongst, RECs.Component analysis is summarized in BOX B: Overview of component analysis as a tool for RECsand researchers.


(Adapted from Weijer & Miller, 2004)

Whether or not RECs choose to use the component analysis approach, they need to ensure thatthe following aspects are adequately addressed (see BOX B: Overview of component analysis formore detail):

If the research proposes to recruit patients into a clinical trial, does the clinical trial satisfyclinical equipoise?Are the risks minimized?If the project involves vulnerable populations, is the threshold of acceptable risk respected?Are the research risks reasonable in relation to anticipated benefits (direct and indirect)?

Prior to approving a project, RECs must be satisfied that the balance of risks and benefits isacceptable. The REC should bear in mind than in many studies there is an ‘asymmetry’ of risksand benefits: the risks are borne by research participants while the benefits often accrue to societyat large. This asymmetry should be offset as far as possibly achievable.

Weijer C., Miller P., 2004.WMA, Declaration of Helsinki, 2013, Para. 8, 16, 17, 20, 28, 33.ICH-GCP, 1996, Sec. 2.2.CIOMS, International Ethical Guidelines for Biomedical Research Involving HumanSubjects, 2002, Guidelines 8, 9.COUNCIL OF EUROPE, Convention on Human Rights and Biomedicine, 1997, Art. 16(ii).COUNCIL OF EUROPE, Additional Protocol to the Convention on Human Rights andBiomedicine, concerning Biomedical Research, 2005, Art. 6.EU Directive 2001/20/EC on Clinical Trials, 2001, Art. 3(2)a), 6(3)b).US 45 CFR 46 Protection of Human Subjects - Common Rule, 2009, Art. 46.111 (a).Brazil, National Council of Health, Resolution No. 466, 2012.


3.7. Informed Consent

Researchers show respect for autonomy by enabling potential research participants to makeinformed choices about whether to participate in research. Likewise, by informing researchparticipants about any new information learned during on-going research that could affect theirwillingness to participate, researchers respect research participants’ autonomy since participantsare given the opportunity to choose to continue to participate or exercise their right to withdraw.Respect for autonomy is so important that violations to people’s personal integrity, for instance, byusing them in research (or even touching them!) without their consent or authorization, are inprinciple forbidden by law.

Is the proposed consent process appropriate?

Obtaining valid consent is critical in showing respect for autonomy since it allows prospectiveparticipants the opportunity to choose to take part in research and to voluntarily expose themselvesto the research risks involved. In conducting ethical evaluation, RECs will want to ensure theproject and consent documentation are appropriate for obtaining valid consent. In order to assessthe appropriateness of the proposed consent process, RECs must understand the key elements ofvalid consent. These are:

1. Persons must be capable: Capacity refers to the mental capacity of the participant toconsider alternatives in light of personal goals, values, and preferences.

2. Persons must be competent: Competence refers to the legal capacity to authorize orrefuse participation.

When prospective participants lack capacity and/or competency to consent additionalsafeguards are required. Minimally, the permission of a legally authorized representative isrequired and in some countries, national law requires assent of the prospective participantwhen possible. In many countries, when able to express oneself, an incompetent person’srefusal to participate must also be respected

3. Persons must be informed: During the conduct of research, participants may be exposedto risks without any potential personal benefits. In this context, it is necessary thatparticipants be informed of all the potential risks. Various guidelines provide lists ofessential information that must be communicated to prospective participants. [See BOX C:Some key elements that should be disclosed] In addition to disclosing information toprospective participants, researchers must also ensure that prospective participantsunderstand and have an appreciation of the information. The role of the REC is critical as itneeds not only to assess whether all the pertinent information is included but also whetherthe language used in consent documents suits the prospective participants’ level oflanguage, whether translations are needed, whether the process is culturally appropriate,etc.

4. Consent must be voluntary: Prospective participants must be free to choose whether toparticipate in a given project and subsequently whether to withdraw from the project. Ingeneral, this means that consent should be free from undue influence, undue inducement,coercion or manipulation that may influence the person’s free choice.

Nuremberg Code: Article 1

The voluntary consent of the human subject is absolutely essential. This means that the personinvolved should have legal capacity to give consent; should be so situated as to be able to exercisefree power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and


comprehension of the elements of the subject matter involved as to enable him to make anunderstanding and enlightened decision. This latter element requires that before the acceptance ofan affirmative decision by the experimental subject there should be made known to him the nature,duration, and purpose of the experiment; the method and means by which it is to be conducted; allinconveniences and hazards reasonable to be expected; and the effects upon his health or personwhich may possibly come from his participation in the experiment.

The Nuremberg Code, 1949, Principle 1.WMA, Declaration of Helsinki, 2013, Para. 25, 26, 31.ICH-GCP, 1996, Sec. 2.9, 4.8.WHO, Operational Guidelines for Ethics Committees, 2000, Sec 6.2.5;CIOMS, International Ethical Guidelines for Biomedical Research Involving HumanSubjects, 2002, Guidelines 4, 5, 6.COUNCIL OF EUROPE, Convention on Human Rights and Biomedicine, 1997, Art.16(iv)-(v).COUNCIL OF EUROPE, Additional Protocol to the Convention on Human Rights andBiomedicine, concerning Biomedical Research, 2005, Art. 13, 14.EU Directive 2001/20/EC on Clinical Trials, 2001, Art. 3(2)b).US 45 CFR 46 Protection of Human Subjects - Common Rule, 2009, Art. 46.109 (b) (d),46.111 (a) (4), 46.116.


3.7. Informed Consent (continued)

Waiver of consent

Researchers should not enrol participants in a trial prior to obtaining their individual consent. Insome very limited and specific circumstances, the consent requirement can be waived by the RECafter careful consideration. This may be the case for emergency or intensive care research. In suchsituations, necessary measures should be taken to seek the patient’s informed consent toparticipate in the research as soon as s/he has recovered her/his full capacity. Both investigatorsand RECs must verify this waiver of consent to research is allowed by law.

A process

Consent should be understood as a process, not a single event. Thus, information about theresearch can be disclosed and discussed on several occasions and in a variety of ways beforesomeone chooses to participate in the research project. The process should continue after theparticipant chooses to participate until the completion of the research project. This requirescommunication of any new information that may affect willingness to continue to participate.

Participants can also choose to withdraw from research participation for any reason. Withdrawalfrom a project should not compromise the rights of the participant in any way – e.g. to accessongoing health services from a research site normally offering health care. In some circumstances,participants’ ongoing consent to continue participating in research should be sought (eitherformally or informally) throughout the research project.

Written or documented consent

In principle, participants should sign a consent form to indicate their choice to participate in aresearch project. In some countries, this is a legal requirement. Written consent may also benecessary if researchers wish to have access to participants’ medical files for research purposes.However, in some situations, written consent is not possible since prospective participants may notbe able to read or write. In these cases documentation, including the consent form, should beexplained verbally (possibly by a third party not involved in the research). Consent may beexpressed in a number of ways. In some rare situations, it is preferable to not have written consentsince without any identifiable records participants can remain anonymous. When exceptions towritten consent are required, researchers must provide justification to the REC which will decide ifthe exception is warranted.

Involving communities and families or spouses within the consent process

In some cultures, researchers may enter a community to conduct research or approachprospective participants only after having obtained permission from the community leader, familyleader or other authority. Investigators should strive to understand and respect such customs.However, community or family leader permission does not in any way replace the need to obtainindividual consent from prospective participants.

Consent by special populations

Consent is a process that raises a number of issues when special populations are considered forresearch: persons with mental disorders, prisoners, military, pregnant women, children, orphans orchild-headed households. Populations such as these may also be in situations of vulnerability anddeserve additional protections because being in a situation of vulnerability can diminish a person’s


ability to participate meaningfully and independently in the consent process or can expose them torisks. If after careful consideration of the proposed study population the REC considers that thereis sufficient scientific justification for including vulnerable populations, then the REC must ensurethat the consent process is appropriate. When prospective participants lack the capacity to consent(minors, incompetent adults) then consent from the legal representative must be sought. Whenprospective participants are competent, but are in situations that affect the voluntary nature of theirconsent, special measures may be required.

Consent for the use or re-use of personal health information and biological material

In principle, individual consent is necessary to collect, use and/or store personal health informationand biological material for research purposes. Consent is also required for any additional uses ofthese data. However, there may be situations where consent would be impossible or impractical toobtain for such research or would pose a threat to the validity of the research. In such situations,and as local regulations provide, it may be possible to conduct such research after REC approvalthat confirms that individual consent need not be obtained.

When reviewing projects involving the collection, use/re-use and or storage of personal informationand biological material, RECs must ensure that either consent will be obtained or that theconditions for waiver of consent are present. To be granted a waiver of subject consent,researchers should minimally demonstrate that consent is either impracticable or impossible, orthat the validity of research would be compromised by a consent requirement. RECs andresearchers will also need to consider applicable regulatory requirements as well as guidelines onepidemiological research such as the International Ethical Guidelines for Epidemiological Studies,2009.

CIOMS, International Ethical Guidelines for Epidemiological Studies, 2009.


3.8. Fair compensation / reimbursement

It is acceptable to offer a certain level of compensation, reimbursement or payment to researchparticipants for their expenses or travel costs due to participation in a trial. They may also receivefree medical services in addition to any medical treatment considered necessary for the safeconduct of a trial. Some guidelines even allow payment for lost earnings although this practice issometimes prohibited by national regulations. When a clinical trial involves healthy volunteers whoreceive no direct benefit, they may be paid for inconvenience and the time spent participating tothe trial. It is not acceptable to pay for risks taken in research.

Does the proposed compensation constitute undue inducement?

However, proposed compensation or reimbursement must be fair and not constitute ‘undueinducement’. Inducement will be considered undue if it could lead to persons undertaking actionsthey would not ordinarily accept. Undue inducement occurs for example, when the payments areso large or the medical services so extensive as to induce prospective participants to consent toparticipate in the research against their better judgment. Undue inducements make consentinvoluntary.

Is the compensation fair?

RECs must use their judgment to assess whether or not compensation is acceptable or undulyaffects voluntary nature of consent. What constitutes fair compensation varies according to theparticular context of each trial and of each type of person being solicited for participation.

“Monetary and in-kind recompense must, therefore, be evaluated in the light of the traditions of theparticular culture and population in which they are offered, to determine whether they constituteundue influence. The ethical review committee will ordinarily be the best judge of what constitutesreasonable material recompense in particular circumstances.” (CIOMS comment to GL 7)

Compensation offered to prospective participants must be documented and approved by the REC.The REC must also consider the compensation arrangements that will apply if a participantwithdraws from the study or is withdrawn by the investigator. It is usually considered inappropriateto make full compensation dependent on completion of a trial.

ICH-GCP, 1996, Sec. 3.1.2, 3.1.8, 5.8.3.WHO, Operational Guidelines for Ethics Committees, 2000, Sec. 5.3.12, 6.2.3.10.CIOMS, International Ethical Guidelines for Biomedical Research Involving HumanSubjects, 2002, Guidelines 6, 7.COUNCIL OF EUROPE, Additional Protocol to the Convention on Human Rights andBiomedicine, concerning Biomedical Research, 2005, Art. 12.EU Directive 2001/20/EC on Clinical Trials, 2001, Art. 6(3)(j).


3.9. Privacy and confidentiality

Respect for privacy requires keeping secret or hidden what is not intended for public view. Animportant aspect of privacy in research ethics is confidentiality, which requires keeping personalinformation secret or hidden. Respect for privacy and confidentiality are important ways to promotehuman dignity.

Confidentiality of information gathered during research

As with any information collected during care by a health professional, personal informationcollected during research must be held confidential. The researcher has a duty not to sharepersonal information about the research participant with others without the participants’ consent ora legal authorization to do so. The duty of the researcher to treat private information in a respectfuland confidential manner is an internationally recognized norm and ethical standard.

Does the project properly protect privacy and confidentiality?

RECs play a critical and essential role in balancing the importance of the activities of researchagainst the respect for privacy. RECs also play an important role in ensuring that invasions ofprivacy are minimized. Privacy involves the “right to be left alone”. Recruitment procedures ofproject should respect prospective participants’ privacy.

One way to protect the confidentiality of personal information and records is to anonymize them(i.e., remove all identifiers). However, access to personal identifying information is essential formany research projects in order to advance knowledge that benefits the participant and society asa whole. When personal information will be recorded, research participants have a right to knowwho will have access to their information. RECs protect this right and protect participants fromharm that may be caused by unauthorized use of personal data by ensuring that participants areinformed, via the consent process, of the extent of the confidentiality that can be promised.Therefore, participants must be informed about who may potentially have access to their identifyinginformation (e.g. the REC, regulatory agencies, the sponsor of the study or funding agencies).

Furthermore, during the ethics review of a research project, the REC should verify that datacollected is stored by the researcher with all appropriate measures necessary to protectconfidentiality based on the sensitivity of the information and see to it that when data is released itdoes not contain names or identifying information.

In its review of research that obtains personally identifiable information about research participants,the REC should consider:

The type of data to be collectedThe purpose for which the data will be usedLimits on the use, disclosure and storage of the dataAppropriate safeguards for security and confidentialityVisual and sound recordings that allow identification of particular participantsWho will have access to the data and whether they promise to respect confidentialityAny anticipated secondary use of identifiable information from the researchAny anticipated linkage of the research data with other data about participants, andProvisions for confidentiality of data in research reports.

WMA, Declaration of Helsinki, 2013, Para. 24.CIOMS, International Ethical Guidelines for Biomedical Research Involving Human


Subjects, 2002, Guideline 18.WHO, Operational Guidelines for Ethics Committees, 2000, sec 6.2.4.ICH-GCP, 1996, Sec. 2.11.COUNCIL OF EUROPE, Convention on Human Rights and Biomedicine, 1997, Art. 10.COUNCIL OF EUROPE, Additional Protocol to the Convention on Human Rights andBiomedicine, concerning Biomedical Research, 2005, Art. 13, 14.EU Directive 2001/20/EC on Clinical Trials, 2001, Art. 3(2)c).US 45 CFR 46 Protection of Human Subjects - Common Rule, 2009, Art. 46.111 (a) (7).


3.10. Researcher conflicts of interest

Properly managing conflicts of interests of researchers, as well as of REC members as seen abovein 1.2, is an important mechanism for promoting the protection of research participants.

What counts as a conflict of interest?

Conflicts of interest can be generally defined as:“a set of conditions in which one’s judgment concerning a primary interest tends to be undulyinfluenced by a secondary interest.” (Thompson 1993)Primary interests of researchers include, for example, patient/research participant welfare orconducting valid research. Secondary interests of researchers could include, for example, financialgain, acknowledgment and professional advancement, or other personal interests. Secondaryinterests are not necessarily illegitimate in themselves but what is problematic is the influence theyexert on decisions. A common conflict of interest arises when the researcher also has routineclinical care responsibilities for the persons he or she recruits into a research study.

Conflicts of interest can be actual, potential or perceived. The appearance of conflict may be asdamaging as a real conflict. While being in situations of conflict does not imply that people aredishonest, it is important that these situations be managed properly in order to promote theintegrity of judgment, to ensure transparency and to preserve the trust relationship researchershold with research participants.

Can researcher conflicts of interests be managed properly?

As a general rule, researchers are required (often on REC submission forms) to disclose actual,perceived or potential conflicts of interest to the REC. Institutions may develop mechanisms toaddress and resolve conflicts of interest. In order to properly evaluate a project, the REC should beprovided with details on budgets, commercial interests, contractual relationships and other relevantinformation.

A conflict of interest can be assessed as severe or not by evaluating the likelihood that theresearcher’s judgment will be influenced by the secondary interest and the seriousness of theharm or wrong that is likely to result from such influence or the appearance of undue influence.

RECs can use two tests to assess the implications of actual, perceived, or potential conflicts ofinterest:1) Would an outside person question the ability of the researcher to make a proper decisiondespite possible secondary interests (financial, personal, etc.)?2) Would the public believe that the trust relationship could reasonably be maintained betweenrelevant parties (e.g., participants and researchers) if they had information on the conflict ofinterest?

RECs can help to manage conflicts of interest by:• raising awareness,• requiring disclosure of interests to all affected parties,• prohibiting the secondary interest, and/or• using continuing ethics review process. (For example, when significant conflicts of interest arebrought to the REC’s attention, it should require that the researcher disclose these conflicts toprospective participants during the informed consent process.)

However, some conflicts of interest compromise the primary interests of researchers or public trust


to such an extent that they are considered unacceptable. For example, the payment of finders’fees to physicians for the recruitment of research participants is considered an unacceptableconflict of interest. Similarly, a contractual clause that unreasonably limits a researcher’s freedomto publish the research results is also considered unacceptable. In such situations, RECs mayrequire the researcher to abandon one or all of the secondary interests.

Thompson D., 1993.Glass K.C., Lemmens T., 1999.


3.11. Scientific integrity

In conducting research involving humans, researchers have important privileges and freedoms.They also have responsibilities associated with these privileges and freedoms. Researchers areexpected to meet high levels of scientific integrity that include accurate collecting and reporting ofdata generated during the research and appropriate use of research funds. Researchers are alsoexpected to publish their research findings and have freedom from censorship.

However, integrity (i.e., the quality of being honest) is not always achieved. Misconduct mayinclude the reporting of unsubstantiated or falsified data, plagiarism, failure to acknowledgesubstantive contributions from other persons, the selective reporting of favourable data, thetrimming of inconsistent data. Such misconduct may result in disciplinary actions againstresearchers.

Are researcher responsibilities during the conduct of a trial made clear?

When the REC approves protocols, researchers should be reminded of, and commit to, theirresponsibilities during the conduct of the trial. These responsibilities include:

Following the protocol and the inclusion and exclusion criteria. Integrity requires thatresearchers adhere to inclusion and exclusion criteria, as these are designed to ensurescientific validity and to ensure protection of participants. Any deviation frominclusion/exclusion criteria to ensure enrolment for a project can harm participants andinvalidate the results of the research.Supervising the research teamReporting serious (unexpected) adverse events to the REC, the sponsor, and any otheragencies that required such informationSubmitting protocol amendments to the REC for review and approval before they areimplemented (unless immediate changes are required to avoid harm to participants).Record keeping according to applicable regulations and national or institutionalrequirementsCommunicating results: if research results are not made public, research has no value.Researchers have a duty to disseminate results to those who served as researchparticipants, to other researchers, and to anyone else who could make use of the results.

WMA, Declaration of Helsinki, 2013, Para. 23, 26.WHO, Operational Guidelines for Ethics Committees, 2000, Sec 6.2.1.8.ICH-GCP, 1996, Sec. 2.6, 2.10, 4.5, 4.9.COUNCIL OF EUROPE, Convention on Human Rights and Biomedicine, 1997, Art. 4.COUNCIL OF EUROPE, Additional Protocol to the Convention on Human Rights andBiomedicine, concerning Biomedical Research, 2005, Art. 8.


3.12. Ongoing respect for research participants and collaboratingcommunities

Research involving humans must be based on a trust relationship if individuals are to continue tovolunteer to participate. Continuing to demonstrate respect for participants and their communitiesafter the project has ended is essential to maintaining the trust relationship. Ongoing respect toresearch participants and collaborating communities is demonstrated by the following actions.

Informing participants of the results of the study

Persons entered into the study are entitled to be informed about the outcome of the study in aformat appropriate to the recipients, and to share any benefits that result from it. Plans to informparticipants of research results should be presented as part of the research protocol.

Providing proper insurance and compensation for damages

Participants who are injured as a result of their participation in a trial must be offered medicaltreatment and compensation for damages. The REC should ensure that the protocol provides forinsurance coverage for such eventualities.

Should the protocol provide access to drugs once the trial is finished?

For some drug trials, participants may benefit from receiving the experimental drug. For example, ifa new formulation of an already approved drug is being tested in a developing country that cannotafford the drug, then it is quite likely that participants will benefit. Sometimes, when new moleculesare tested, Phase III trials will demonstrate benefits for patients. When it reviews protocols, theREC should consider whether participants should continue to have access to the trial drug after thetrial is completed. These aspects must be discussed before a project starts.


Part 4. Documents to be reviewed

The nature of research projects varies from one project to the next. Ethics evaluation practices alsoevolve over time. Hence, it is difficult to establish a definitive list of documents that the REC needsto conduct a full evaluation. Given the nature of ethics evaluation, the REC may ask to be providedwith any document it considers important.

Certain documents are commonly required by the REC for evaluation. These include:

The completed REC application form, signed and dated by the investigatorThe updated full protocolInvestigator brochure (if applicable, but compulsory for clinical trials unless the relevantinformation is already incorporated into the protocol)Information sheets and informed consent documents (including any documents that will beprovided to participants)Documents on the investigator’s qualifications (e.g. CV and licences)Financial arrangements for the site (e.g. any compensation for participants and fundingsource for the study)Any questionnairesAny material to be used for recruitment

Examples of other documents that may be required by the REC for evaluation include:

Any other REC decisions, both positive and negative (in case of multi-centre studies)Full study site budgetRelevant contracts/agreements (e.g. study site agreement/investigator’s agreement)

When the project involves an experimental drug, vaccine or device, the investigator should alsosubmit any government authorizations and registrations that are required.

When the research is funded by private industry, the REC should be provided with any contractualclauses that may have an impact on the ethical acceptability of the project. These include anyclauses that:

are relevant to any indemnity in case of injuryare relevant to the insurance coverage for research participantsaffect publication of results

The ICH-GCP provides specific guidance on the content of protocols for clinical drug trials (seeGCP section 6). To ensure it receives information on precise aspects of projects it evaluates, theREC may want to request specific information in their submission forms. For example, asubmission form may ask for:

a summary of the protocol in non-technical languagea summary of potential benefitsa description of the ethical considerations,a description of the recruitment process and of the consent processprecisions that may be required by national law

WMA, Declaration of Helsinki, 2013, Para. 22.WHO, Operational Guidelines for Ethics Committees, 2000, Sec 5.3.ICH-GCP, 1996, Sec. 3.1.2.


CIOMS, International Ethical Guidelines for Biomedical Research Involving HumanSubjects, 2002, Appendix 1.COUNCIL OF EUROPE, Additional Protocol to the Convention on Human Rights andBiomedicine, concerning Biomedical Research, 2005, Art. 11, Appendix 1.

Powered by TCPDF (www.tcpdf.org)


Module 2.1 Training and Resources in Research Ethics ...

Documents

Transcript of Module 2.1 Training and Resources in Research Ethics ...