Co-enrollment of patients in trials of complex surgical interventions: Recommendations from the intact trial

Issue: Co-enrollment of patients in trials of complex interventions is an emerging phenomenon. Co-enrollment can provide efficiencies, pertinent in the era of a pandemic, but is not without issue. Management of patient co-enrollment, especially in trials investigating multiple interacting components, such as surgical randomized controlled trials, is considered. Setting: IntAct is an international surgical trial which has recruited throughout the COVID pandemic. It is a prospective, parallel group, randomized controlled trial comparing surgery with intraoperative fluorescence angiography against standard care (surgery alone) to determine the effect on anastomotic leak in patients undergoing resection for rectal cancer. Co-enrollment of patients has been requested by nine other trials to date, ranging from interventional drug trials to observational studies. There is minimal published literature regarding co-enrollment to inform discussion and decision-making by the IntAct Trial Management group. Background: Co-enrollment of patients in clinical trials poses a number of potential issues spanning ethical, safety, statistical, and practical concepts, which require careful consideration. Effort has been made to quantify the potential impacts of co-enrollment on statistical power (Myles, 2014). For example, the interaction of treatment effects and substantial or imbalanced co-enrollment have been shown to possess the potential for a large detrimental effect on the sample size. In practice, the nature of such an interaction, or the level of co-enrollment, will not be known in advance. Furthermore, where the intervention is complex in nature, such as in surgical trials of multiple component parts like IntAct, not only is there the possibility of an interaction between the treatment effects of co-enrolling interventions, but also of how the co-enrolling intervention may alter the individual intervention components. There is no published guidance on how to assess these risks a priori. Nonetheless, there are also many potential benefits to allowing co-enrollment. These include increased availability of research opportunities to patients and increased efficiencies to sites when patients contribute to multiple research projects. Disallowing co-enrollment could pose a risk to a trial's recruitment by narrowing the pool of potential participants. Likewise, there is no published guidance on how to assess these benefits a priori. Key considerations for co-enrolling trials: the IntAct Trial Management group decision-making process was informed by discussions regarding: • Internal validity: the ability of the co-enrolling intervention to change the typical operative setting, as well as the post-operative care pathway. • Potential interaction of treatment effects: particularly with regard to the primary endpoint and participant safety. • Generalizability: the possible implications for the trial results. • Recruitment impact: the probable restrictions imposed if co-enrollment was disallowed. • Compliance: the likely effects of co-enrollment on data collection, follow-up visits and withdrawal, and ethical considerations of overburdening participants. We present our rationale and recommendations for guiding Trial Management group discussions when considering and approving co-enrollment of patients in clinical trials. By presenting the experiences of the IntAct international surgical trial Trial Management group, we provide a practical reference for trials considering co-enrollment.

Response of tertiary addictions services to opioid dependence during the COVID-19 pandemic.

The emergence of the COVID-19 pandemic has presented the addiction services with an unprecedented set of challenges. Opioid users are particularly vulnerable because of their high level of pre-existing health problems and lifestyle factors. In order to minimise their risks to self and to others in the current Covid-19 crisis, addiction services sought to urgently identify vulnerable individuals, and induct them into opioid substitution treatment (OST) promptly. Additionally, several guidelines were created and regularly updated by the health and safety executive (HSE) for any healthcare staff working with opioid users. These include guidance documents, to facilitate prompt induction of patients onto the OST programme, the prescribing of naloxone to all patients at risk of overdose, eConsultation, medication management for those in self-isolation, and the delivery of injecting equipment. The guidance documents and resources will provide a template for a new way of working for the sector during these challenging times and into the future.