independent data monitoring committee (DMC) has been formed to monitor data and safety as this is a large clinical trial with multiple study sites. The DMC consists of subject matter experts who are not part of the EXPEL study team. An interim analysis will be performed after at least 200 subjects have completed 6‐months follow‐up. The purpose of the interim analysis is two-fold: firstly, to mitigate the risks from this trial should any unexpected serious adverse effects surface. Secondly, to allow for preliminary analysis of data to assess the efficacy of EIPL as compared with standard therapy. This would allow early closure of the trial should the efficacy be unequivocally proven, or modification of the trial with regard to increasing the sample size should it be deemed inadequate to show a more modest improvement in OS.
3.11 Ethical issues
There are both general and specific issues that should be addressed in this section. These may range from ensuring that the protocol conforms to the internationally agreed Helsinki agreement and more recent Good Clinical Practice (GCP) regulations that have been adopted by many countries, through to obtaining local approval of the informed consent processes being applied.
3.11.1 General
There are internationally agreed standards under which clinical trials are conducted and these are encapsulated in GCP which is referenced as ICH E6 (R2) (2016). Then there are the more specific requirements, perhaps national as well as local, that must be adhered to. The precise details of these will vary with the trials’ geographical location, whether single or multicentre in design; local, national or international; the type of interventions under study, and the intended target participation groups.
Example 3.23 Protocol PRESSURE (2000): Pressure‐relieving support surfaces: a randomised evaluation
The study will be conducted in accordance with the Declaration of Helsinki in its latest form. The study will be submitted to and approved by a Regional Multicentre Research Ethics Committee (MREC) and the local Research Ethics Committee (LREC) of each participating centre prior to entering patients into the study. The NYCTRU will provide the LREC with a copy of the final protocol, patient information sheets and consent forms.
The conduct of the trial will be monitored by a Trial Steering Committee consisting of an independent Chair and two independent advisors as well as the project team (Appendix H).
Note this statement acknowledges that the trial development team are aware of potential updates of the Declaration of Helsinki. This will also be the case for any of the regulatory and other codes of practice that may pertain, as these too are continually being revised to meet new circumstances. However, if regulatory changes are made, they may or may not be invoked for ongoing protocols that have current approval status.
A major ethical requirement is to ensure that the potential participants in trials understand that participation is voluntary, and that they are free to withdraw their consent at any time and that doing so will not in any way compromise the future treatment that they will receive.
Example 3.24 Protocol SQGL02 (1999): Brimonidine as a neuroprotective agent in acute angle‐closure glaucoma
The right of the patient to refuse to participate without giving reasons must be respected. After the patient has entered the trial the clinician must remain free to give alternative treatment to that specified in the protocol at any stage if he/she feels it to be in the patient’s best interest. However, the reasons for doing so should be recorded and the patient will undergo an early termination visit for the purpose of follow‐up and data analysis. Similarly, the patient must remain free to withdraw at any time from protocol treatment without giving reasons and without prejudicing his/her further treatment.
3.11.2 Informed consent
Before any trial can take place, individual subjects have to be identified, and formal processes for their consent will have to be instituted. The precise details will depend on the type of trial contemplated, for example, whether it involves an invasive procedure, concerns primary intervention, or has therapeutic intent. Also, if it involves participants such as children, the very elderly, healthy volunteers, the terminally sick or women of fertile age then this may raise particular issues, for example, requiring proxy consent, or reassurance that the trial drugs will not compromise subsequent fertility.
Importantly the patient (or the consent giver) should understand that no‐one knows in advance which therapy will be allocated, and that they should be willing to accept whatever the allocation may be. If they are unwilling, they should not be recruited to the trial.
The ideal is that each patient or volunteer gives fully informed and written consent. However, departures from this will be appropriate in specific circumstances. For example, such departures may concern patients that are unconscious at admission to hospital, patients with hand burns that are so severe that they affect their ability to provide their signature, very young children or those mentally compromised. In these cases, a proxy may consent for them or in the case of those with severe burns witnessed verbal consent may be substituted.
Example 3.25 Protocol SQGL02 (1999): Brimonidine as a neuroprotective agent in acute angle‐closure glaucoma
Before entering patients on the study, clinicians must ensure that the protocol has received clearance from their local Ethics Committees. The patient’s consent to participate in this trial should be obtained after full explanation has been given of the treatment options, including the conventional and generally accepted methods of treatment, and the manner of treatment allocation.
All the possible options on trial should be explained impartially to the patients concerned. This explanation must be provided before the randomisation is realised as knowledge of the assignment may influence the way in which an investigator explains the alternatives. A key feature of the informed consent process is to explain the randomisation procedure and to emphasise that participation is completely voluntary and that the patients can withdraw from the protocol at any time.
As is often the case, new challenges arise and the 2020 COVID‐19 pandemic has had a profound and immediate impact on the conduct of clinical trials. Even without the lockdown and the introduction of circuit breaker in place, due to the infectious nature of the corona virus, it was deemed that the risks would be too high to continue with research activities requiring face‐to‐face contact. As a consequence, in a proposed cluster randomised trial to be conducted in Singapore on the safety and efficacy of hydroxychloroquine in households with index COVID‐19 cases, the study team proposed to contact those concerned via telephone to assess their interest to participate in the clinical trial. At the same time, the email address of the household contact would be obtained. Once the eligible participant had ample time to read the electronic informed consent form (e‐ICF), the study team would conduct the informed consent discussion via video consultation. If the subject then wished to take part in the trial, he/she would be required to digitally sign the e‐ICF using Docusign, in the presence of an impartial witness during the video consenting process.
Example 3.26 eConsent – acute stroke
Haussen, Doppelheuer, Schindler, et al. (2017) describe the use of an electronic consent (e‐Consent) tool to facilitate the informed consent process in trials involving patients with acute ischemic stroke. Because of impairment of language and cognitive status in these patients, the requirement of a physical signature of a legally authorised representative during the consent taking process
