By Dr Aw Swee Eng

Some years ago a proposal was received by a hospital’s Institutional Review Board (IRB) to test a new drug for dissolving blood clots.

Such proposals are routinely received by IRBs as part of efforts to improve health care. This drug had been used by hospitals abroad and if it worked well, would be a boon for stroke patients.

The IRB studied the proposal but found there was insufficient evidence that the drug was safe. The proposal was rejected.

Two years later, research from overseas institutions reported adverse effects from the drug, which acted too strongly on blood clots, causing bleeding in the brain at the site of the clot. This proved the IRB had been correct in its decision.

What is the IRB?

Doctors and their colleagues who carry out clinical research apply ethical principles when they make decisions affecting patients or volunteers who take part in their studies.

Ensuring that ethical principles are adhered to in research is the function of the independent IRBs, also known as Research Ethics Committees.

In Singapore, these principles are enshrined in the Singapore Guideline for Good Clinical Practice issued by the Ministry of Health. The Health Sciences Authority oversees the functions of IRBs.

The Republic’s Bioethics Advisory Committee has also issued a report containing helpful recommendations on research involving people.

Ethical guidelines are, for the most part, based on the internationally accepted code of ethics for human biomedical research called the Declaration of Helsinki, drawn up by the World Medical Association in 1964 and revised periodically.

Singapore Health Services (SingHealth) and the National Healthcare Group have their own group of five IRBs. Each is made up of eight to 10 members including at least one lay person.

How the IRB functions

When an investigator decides to begin a clinical trial to test whether a new drug is effective and safe for treating a disease, he must first submit a protocol to the centralised IRB Secretariat.

A protocol is a detailed plan explaining the objectives of the research and how it is to be carried out.

Without the IRB’s written approval, he cannot begin his trial. The IRB may halt a trial if it finds that he has failed to comply with the terms stated in the protocol, or if it is convinced that the subjects’ welfare and safety are compromised.

In the simplest form of a clinical trial, one group of patients (called the treated group) receives the drug. A second control group receives the current standard drug for the particular disease. In some trials, a third control group will receive a placebo – an inactive substance.

Placebo controls sometimes replace the second control group. Volunteers do not know if they are taking a placebo or medicine.

Patients are allocated to a test or control group randomly. The whole trial is now called a randomised controlled trial.

Better organised trials are also “blinded” – neither the doctor nor the patient knows to which arm the patient belongs. This cancels the effect of any bias in the way the patient or the investigator responds to the treatment.

When it reviews a protocol, the IRB first has to study various issues in the interests of patient safety and well-being.

The proposed research should be conducted by qualified persons who have training and experience in clinical trials and in the skills needed for any new procedure being investigated.

The perceived benefits of the new treatment should also outweigh the possible risks. All medicines have side-effects. These usually become obvious in very early experiments in animals and human volunteers. Comparisons with drugs of similar chemical structure already in use also give clues as to undesirable reactions.

It is up to investigators to see if adverse reactions could cause physical or mental distress, and to make sure a patient is not given a treatment known to be inferior to established therapies.

Safety is of paramount importance. The IRB examines the available information on the properties and history of use of the new drug. This includes whether it has been tested rigorously in the laboratory and, where appropriate, in cell cultures, animals, as well as preliminary studies in people.

Recruiting subjects for trials

Another consideration is the recruitment of subjects. How do the doctor and his team plan to recruit patients? Who actually recruits, and where will recruitment take place? What are the criteria for deciding who takes part in a trial?

Researchers must adopt rules at the outset of a study on when to stop when certain agreed outcomes are reached. Commercially initiated trials often employ data and safety monitoring boards to oversee the way a trial progresses.

These panels may stop a trial because people in one arm of the study are doing far worse than others.

Finally, there should be a patient information sheet that fully and objectively explains all relevant aspects of the trial in such a way that if the patient consents to participate, that consent is given freely.

Enrolling a person as a research subject is justified only if that person, or someone authorised to act on his behalf, understands the process and consents in writing.

It is important to realise that obtaining consent is a continuing process rather than a single event that ends with the signing of a form. If conditions affecting the trial change – for instance, because of fresh evidence of the medicine’s efficacy – the patient has to be told. Depending on the nature of the new findings, authorisation by the patient to continue in the trial may have to be renewed.

Special attention is paid to obtaining informed consent from vulnerable people who lack the ability to make informed choices about themselves. These include children, expectant mothers and people with impaired mental ability.

Patients must be told the facts in simple, non-technical language that is easy to understand. This generally includes the purpose of the research and the procedures to be undertaken, including the randomisation process.

The possible benefits to the patient and to medical science must be explained, together with the foreseeable risks, discomforts and inconveniences.

Should blood, urine and tissue samples be taken, they must be told how much will be needed, and how frequently, as well as what happens to these samples, how they will be stored and for how long.

The patient must also be informed that he is free to say no, or withdraw from the study at any time without penalty.

The patient needs to be assured that all data, medical and genetic, will be kept confidential, unless required by law to be disclosed.

Patient Information Sheets will also contain information on payment arrangements for subjects entered in the trial. The amounts paid compensate for travel, meals and the inconvenience due to time and effort spent beyond normal visits to the hospital. The IRB ensures that financial inducement does not unduly distort the judgment of the subject as to his or her participation in the trial.

Clinical research is essentially a communal venture, as members of our society are being asked to assist in research.

This is an important reason for including lay members in IRBs, so that the professionals in health care can benefit from their insight and feedback.

Researchers must regard those who register for their trials as partners. In this way they can work together with respect and candour to achieve their goals.

The writer is chairman of SingHealth’s Centralised IRB, senior consultant and past head of the Department of Nuclear Medicine and PET (Positron Emission Tomography) at Singapore General Hospital.