Ethical Review Process by Ethics Committees

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Course:	Ethics
Book:	Ethical Review Process by Ethics Committees

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Date:	Friday, 26 April 2024, 4:02 PM

1. Authority, Role and Mandate of Research Ethics Committees (RECs)
2. What Research Requires Ethics Evaluation?
- 2.1. Particular Cases
- 2.2. Levels of Evaluation
3. Documents To Be Reviewed By RECs
4. Disclosure to Prospective Participants

1. Authority, Role and Mandate of Research Ethics Committees (RECs)

(This section is organised in the form of a book, please follow the blue arrows to navigate through the book or by following the navigation panel on the right side of the page.)

Research Ethics Committees (RECs) are sometimes referred to as Institutional Review Boards (IRBs), Research Ethics Boards (REBs), Independent Ethics Committee (IEC) or simply Ethics Committee (EC). The legal status of RECs varies from country to country and they may be set up, and operate, according to different models. Most frequently, RECs will be set up by a government or an institutional authority (such as a hospital, research institution or university).

In some cases, RECs may be set up by private organisations. However, some countries do not allow ‘private RECs’ that are not publicly accountable in some way (such as through accreditation). There is, however, little hard data to suggest that the quality of ethics review conducted by private RECs differs from that of institutional or national RECs.

Despite legal and operational differences, the primary role of RECs remains the same:

to ensure the well-being, safety and protection of persons who participate in all types of research involving humans.

Ensuring this protection involves collaboration between RECs and researchers to ensure that research meets the highest ethical standards.

RECs will typically accomplish this goal by the combination of the following activities:

Ethics review and favourable opinion before the research starts.
The continuing review of ongoing research.
The active promotion of principles of ethics through education and training.

1.1. Independence of RECs and Committee Members

In order to properly perform their protective function, RECs must be independent from research sponsors, investigators and from any undue influence, such as political, institutional, professional or commercial.

REC independence is critical to ensuring that research participants’ interests always come first and are not secondary to other interests such as scientific advancement or economic gain. REC independence is one of the four requirements for standardised ethical review. The others are constitution, competence and standard operating procedures - these are described later in this lesson.

Achieving REC independence is a challenge in many situations and is often a question of ensuring the following: • Proper accountability (i.e. making sure the right people are responsible) • Balanced membership (i.e. making sure the right mix of people are involved). RECs’ independence is promoted when they are made accountable as will be discussed below. In many countries, it is standard practice to exclude persons of authority within an institution or research centre from being a member of the REC.

A common example of a potential conflict of interest is when an international institution wishes to conduct a collaborative research project, e.g. with institutions in other countries. The foreign collaborating institution typically discusses the issue with the head of the local institution. It might be that the local institution will gain from participation in a trial sponsored by the foreign institution (e.g. a laboratory, equipment, employment). This could be a potential conflict of interest, i.e. if the head of the local institution was to sit on an ethics committee they would not appear to be objective. It is for this reason that many countries in such case do not allow heads of local institutions to sit on RECs.

REC members must also be in a position to conduct independent reviews of protocols. This means that they must be free from, or have declared and properly managed, any conflicts of interest.

If members have particular links with a given protocol, they should not participate in decisions concerning that protocol. Current practice requires them to declare the conflict of interest and they may be asked to leave the meeting room when that protocol is being discussed.

1.2. Composition and Operational Aspects

RECs are multi-disciplinary committees, drawing on the strengths of their members with varied backgrounds. The goal of a diversified membership is to ensure that RECs can collectively conduct a thorough and independent ethics evaluation of research projects.

Although specific requirements vary greatly across Europe, for a typical composition of REC membership is:

At least 5 members who collectively have the qualifications and experience required to ensure proper review of the ethical, scientific, medical and financial aspects of a trial.
At least one lay person, from a diverse educational (social sciences, law, etc.) and social background, as well as ensuring gender balance.

In many countries, it is further required that there be three non-scientific members: one legal, one ethicist and one representing the community.

REC members should be appointed for a fixed term by the recognised authority according to an established procedure. The REC may choose to invite outside experts who are not members to assist on particular aspects (often scientific) of a project.

1.3. Properly Constituted RECs and Standard Operating Procedures

The REC must be properly constituted and function according to applicable guidelines and regulations. It must also perform its functions according to its own written operating procedures.

Minimally, the following elements of any REC should be clearly established:

The authority which established the REC (Terms of Reference).
The REC’s mandate, i.e. its function and duties (Standard Operating Procedures - SOP).
The REC composition, minimum ‘quorum’ requirements, i.e. the minimum number of people required to attend and vote in order to make a valid decision.
The procedure for appointing members.

Guidelines, and in some countries regulations, specify that REC operating procedures should cover at least the following aspects:

How meetings will be conducted, including scheduling and notifying members - this should also include the need to keep detailed minutes of meetings.
How to submit an application to have a proposal reviewed, including the submission form.
That the REC will make its decisions at announced meetings, a minimum number of people must be present in order for a decision to be made.
Process for ethics review, including:

initial review and continuing review of studies,
expedited (rapid) review procedures,
target time for notification of the decision to investigators (in the EU, timelines are mandated by 2001/20/EC).

A rule that no participant should be signed up before the REC has issued its written favourable opinion of the trial.
The investigator’s duty to promptly report to the REC:

deviations from the protocol to remove immediate hazards to participants,
changes that affect the initial balance of risks and benefits,
serious and unexpected adverse drug reactions (ADRs),
any new information that may have an impact on safety of participants or the conduct of the study.

RECs need to ensure their written procedures comply with their national, local or institutional legislation and requirements.

1.4. Ethical Deliberation and Decision-Making

Ethical Deliberation

For members of the REC, ethical deliberation refers to reflection (careful consideration) and discussion of research projects. This process should take into account the ethical principles and values of research ethics from relevant local and international guidelines. During the discussion, all members present should contribute and provide their expertise and perspectives. In order for each member of the committee to do this in a meaningful way, all documentation relevant to the review must be received and reviewed by all members before the discussion. Members must have enough time to communicate their points of view during the discussion. Sometimes different ethical norms and concepts appear relevant but lead to contradictory conclusions, in these cases a significant amount of reflection is required.

Reaching a Decision

Reaching a decision is the second phase of decision-making.

In conducting their review, RECs usually evaluate aspects of the project:

Scientific validity.
Ethical and financial aspects.
Consent documentation.
Expected benefit vs burden/risk.
Any other documents to be provided to participants.

These are described in the following sections. The REC has the authority to make the following decisions about research under their jurisdiction (authority) according to whether it meets ethical requirements:

Provide favourable opinion.
Provide negative opinion.
Request modifications.

This applies to both proposed and ongoing research.

Consensus

Ideally, the REC deliberates and eventually comes to a collective opinion (or consensus) that all members find ethically satisfactory. Consensus reached by a REC is valid as long as it emerges out of deliberations that are honest, fair, and factually well-informed and follow standard operating procedures. However, in reality it doesn’t always work this way. Sometimes a decision is not ‘thoroughly acceptable’ to some members, but those members agree their concerns were heard and discussed, and they regard the process of deliberation and decision-making fair.

Voting

Making decisions by vote, as opposed to consensus, should be restricted to exceptional circumstances. This is because voting gives priority to the number of people who hold a certain opinion but does not take into account the reasoning behind the opinions held. A minimum quorum is required (and should be defined in the SOP) for voting in order to make a valid decision.

1.5. Dissenting and Abstaining

If a minority of REC members consider a project or some aspect of a project unethical, the REC’s operating procedures may state that an effort must be made to reach consensus. However, when a decision reached is not unanimously accepted by all members, the number of members dissenting and/or abstaining should be recorded in the minutes.

Dissenting members are those that do not agree with the majority decision.
Abstaining members are those that decide not to give their vote to either alternative.

Dissenting or abstaining members may also be offered the opportunity to join their opinion to the REC’s decision in a minority report.

1.6. Due Process

From a practical perspective, due process implies that:

The REC will be impartial.
It will make its decisions at announced meetings with a quorum.
Only members who participate in deliberations will take part in decisions.
Investigators/sponsors should have a fair opportunity to be heard (although not participate in the deliberation and decision).

A decision (favourable or negative opinion) should be communicated in writing to the applicant and to the relevant authorities according to national requirements.

Appropriate archiving of records also promotes due process. The REC should ensure that it retains, and be ready to make available, relevant records of its decisions, procedures, etc., for the required time period.

1.7. Follow-up Of Ongoing Research

RECs evaluate research projects initially as part of the decision process. They then re-evaluate ongoing research at regular intervals. With consideration of the researcher’s suggestions, it is left to the discretion of the REC to determine the frequency of follow-up - or continuing review - of ongoing research. This would be based on the level of risk the project poses to human participants.

As part of the continuing review process, examples of events or instances that trigger the need for follow-up by the REC:

Any protocol amendment which is substantial and likely to have a significant impact on the safety or physical or mental integrity of the clinical trial participants or the scientific value of the trial.
Serious and unexpected adverse events related to the conduct of the study or study product, and the response taken by investigators, sponsors, and regulatory agencies.
Any event or new information that may affect the benefit-risk ratio of the study.

The goal of continuing ethics review

The purpose of continuing ethics review is to find out if the research (including recruitment and informed consent process) is being conducted in compliance with the approved protocol. The review will also confirm that the potential benefits and burdens to research participants remain acceptable. If the burdens and/or potential benefits have changed, the participants should be informed of the change. They should then be asked to re-consent to the study, confirming their continued choice to participate in the research. They may also refuse to continue participation.

REC decisions during continuing review

If anything observed during follow-up is found to be unacceptable, the REC might:

Suspend or withdraw favourable ethical opinion of the research (until further information is provided and reviewed).
Request that new information, changes to the research, or changes to the balance of burdens and benefits be communicated to research participants to enable an informed choice or refusal to continue in the research.
Request modifications to the project or to the Informed Consent Form, which will require re-approval by the REC and a new informed choice or refusal from participants.

1.8. Accountability

Given their important role, RECs must be accountable for their work. This can be achieved in several ways.

First, RECs are immediately accountable to their constituting authority. This authority will require annual reports of activities. The constituting authority must also be committed to not overriding a negative REC opinion.

Second, RECs must demonstrate accountability towards researchers and the broader public. This can be achieved by promoting the transparency of its activities and decisions. For example:

Guidelines for how to make an application should be freely accessible.
REC members should evaluate research at officially announced meetings to allow researchers the opportunity to be heard.
Opinions of RECs should be justified and well communicated.

Third, authorities or sponsors of clinical trials and research may inspect/audit a trial site. This may also include the REC that reviewed the research. In such cases, inspectors/auditors will look through minutes of meetings as well as records related to the research.

2. What Research Requires Ethics Evaluation?

Generally speaking, all research that involves humans must be evaluated by a REC. This must happen before the research begins or, more precisely, before any prospective participants are contacted for recruitment. This is often referred to as the ‘ethics review requirement’.

The ethics review requirement also applies to research conducted with personal information found, for example, in medical files, or with human tissue and products such as genetic material.
Research with gametes (mature male or female sexual reproductive cells, i.e. sperm or egg), embryos and foetal tissue also requires prior ethics review in addition to a number of other requirements.

In some countries, certain types of research may be exempt from the ethics review requirement under certain conditions. Some examples of this are:

When research ‘involves only negligible risk’ - i.e. there is no foreseeable risk of harm or discomfort to participants and any foreseeable risk involves no more than inconvenience to participants.
When research ‘involves the use of existing collections of data or records that contain only non-identifiable data about people, e.g. publicly accessible records, archives or publications’.

The REC will assess if research qualifies for one of these exemptions. A researcher cannot issue their own exemption for a study. An exemption must be issued by an REC.

Clinical trials are a good example of a type of research that has additional requirements. In Europe, sponsors of clinical trials for medicines must ask the National Competent Authority (NCA) for authorisation to use an investigational medicine in a trial. Investigators are legally required to have both the NCA approval for use of an investigational medicine and REC favourable opinion before a trial can start.

It is particularly important to note that research that is not scientifically sound is not ethically acceptable. This is because it will expose participants to the burden and potential harms of research without having the possibility of yielding benefits to the participants and/or to society. Thus, the REC must ensure that appropriate scientific evaluation has occurred even if it does not conduct the scientific assessment itself. If research does not pass scientific evaluation, then it should be denied a favourable ethics opinion as well.

2.1. Particular Cases

In some countries, research involving human reproductive material (stem cells, gametes, embryos) is forbidden. Where this is not the case, there will often be a requirement that national oversight committees review the research project in addition to the competent REC.

2.2. Levels of Evaluation

It is generally accepted that RECs can adopt a proportionate approach to ethics evaluation. In other words, the greater the burden of research, the greater the scrutiny. In practice this means that RECs can use two approaches to ethics evaluation:

Evaluation by the full committee.
Evaluation by a sub-committee, which is also called ‘expedited review’.

If the operating procedures of a given REC allow, research that poses only minimal burden can have an expedited review. Minimal burden in this context is when the amount of harm expected in the research is less than that ordinarily encountered in daily life, or in routine medical, dental, or psychological exams. Research that poses greater burden deserves attention by the full REC to ensure proper safeguards are in place.

Full committee evaluation will involve all members’ comments and discussion of all ethical issues arising from the proposed research. Deliberations will take place and members will aim to reach a consensus on the REC decision. This will take place in an ordinary REC meeting, scheduled according to the standard operating procedures.

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

The nature of the applications, amendments and other considerations that will be eligible for expedited review.
The quorum requirements for expedited review.
The status of opinion - i.e. whether or not the opinion still needs to be confirmed by the full committee.

In some countries national regulations establish categories of research that pose no more than minimal burden that can receive expedited review.

3. Documents To Be Reviewed By RECs

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

The REC must review:

The protocol,
The investigator's brochure,
The adequacy and completeness of the written information to be given and the procedure to be followed for the purpose of obtaining informed consent and the justification for the research on persons incapable of giving informed consent as regards the specific restrictions laid down in Article 3, 2001/20/EC,
Provision for indemnity or compensation in the event of injury or death attributable to a clinical trial,
Any insurance or indemnity to cover the liability of the investigator and sponsor,
The arrangements for the recruitment of participants.

For a full list of the review process and timings please refer to Article 6, Directive EC 2001/20/EC.

The ICH-GCP provides specific guidance on the content of protocols for clinical trials. To ensure it receives information on precise aspects of research it evaluates, the REC may want to request specific information in their submission forms. For example, a submission form may ask for:

A summary of the protocol in non-technical language.
A summary of potential benefits.
A description of the ethical considerations.
A description of the recruitment process and of the consent process.
Actions that may be required by national law.

4. Disclosure to Prospective Participants

The following are some key elements that should be disclosed to prospective participants:

The invitation to participate in the research.
Research aims and methods.
Identification of researchers and sponsors.
Sources of funding.
Any possible conflicts of interest, including institutions that the researcher is linked to.
The anticipated benefits of the research.
Alternatives of the research intervention that are already available (if applicable).
Potential risks of the research.
The right to abstain (withhold) from participation in the study or to withdraw consent to participate at any time without reprisal.
Measures taken for the respect of the privacy of participants and for the confidentiality of records in which participants are identified.
Kind and amount of any compensation.
The address of who to contact at any time for more information.
Access to free treatment in case of injury from research procedures and compensation of resulting impairment, disability, and handicap.
Access to interventions identified as beneficial in the study or access to other appropriate care or benefits.