Strategies for managing paediatric patients in immunoglobulin clinical trials

Clinical trials in paediatrics pose several challenges relating to subject recruiting, consenting, and sustaining participation in the trial. Clinicians have unique recruitment challenges relating to the need for parental consent for a minor and the need for the child’s assent. In addition, participation in a clinical trial may place an increased treatment burden as compared to the standard treatments for families. Reasons for non-participation may include safety of the interventional product, frequency of invasive procedures such as blood draws, and more time missed from school and work due to participation (Denhoff et al. 2015).

Despite these challenges, it is important to have children enrolled in immunoglobulin trials as it informs our knowledge about the safety, tolerability, and efficacy in children. Adopting child-friendly strategies to facilitate immunoglobulin trials can lead to the successful participation of paediatric subjects (Macrae 2009). Our centre has successfully conducted clinical trials with immunoglobulin products since the 1980s in paediatric patients. This paper discusses some strategies that we utilize to ensure successful immunoglobulin clinical trials in this unique patient group.

Ethical research requires informed voluntary consent for it to be conducted. In paediatrics, there is the additional need for agreement or assent by the child, if of an age to comprehend the implications of participation (Macrae 2009). Developing standardized approaches to communication about the study is an important tool to foster enrollment. Discussing proposed research with parents and the child prior to screening visits and giving them time to discuss as a family if they are interested in participation is helpful. This discussion should include details of the risks and benefits of participation over the standard treatment. It is important that they understand what is expected of the child during the study as compared to their standard immunoglobulin treatment, so that they fully comprehend what they are committing to (Shilling et al. 2011). Allowing for the opportunity to review consent and assent forms prior to screening visits is required by many ethics boards and allows for the family to come to the visit prepared with questions about the research. This requirement can be met by providing families with consent and assent forms at clinic visits, or via telephone and e-mail communications. In our experience, families are often concerned that the standard treatment will not be available to them once the trial is completed. Providing assurance that participation in the trial will not affect their ongoing care in discussions about the trial can alleviate concerns.

If additional visits are required for the study, the discussion should include who will cover the participation costs for the family i.e., parking, gas, and food. Most clinical trials allow for these expenses to be reimbursed to the family up to a maximum amount per visit. Motivations for study participation in children of different ages may vary: recognizing study contribution by documenting volunteer hours for teens, while some older children like the idea of completing a diary as part of the study, and younger children like to receive certificates as acknowledgement of their participation (Denhoff et al. 2015).

Research requires very stringent documentation of study procedures at every step of the process. Records of study processes need to be very clear for audits by sponsors and regulatory authorities (FDA 2019). At consenting visits, we utilize a standard checklist for clinical trials consent so that researchers cover all aspects of the consenting and assenting process to ensure that it is informed and voluntary. This checklist can be signed and entered into the patient chart as proof of the consenting process for monitors. For institutions that utilize electronic charting, progress notes utilizing smart phrases for consent, screening visits, and study visits can facilitate documentation (ICH 2019).

At screening, there needs to be documentation of what was done at the visit, including review of past and current medication, physical examination, and any additional screening procedures such as laboratory testing and diagnostic imaging. At subsequent infusion visits, documentation should include all required study procedures, including laboratory assessments. For immunoglobulin studies, it is important to ensure that specific information relating to the investigational product, including the condition of the product prior to infusion, temperature of the product (if room temperature is required by the protocol), the lot number, expiry date and time of start of infusion, as well as any interruptions to the infusion are recorded in the subject chart. In addition, all regulatory documents relating to dispensing of the investigational product must be completed in the pharmacy/blood bank where the product is stored and dispensed. This documentation includes lot numbers and vials used for individual subjects, information regarding temperature storage, logs of temperature monitoring, and dispensing information. For every stage of a clinical trial, standard documentation templates assist in successful trials (ICH 2019).

Most immunoglobulin trials require a diary of interim health issues to be completed by the child and (or) family. Diary completion needs to be reviewed at every study visit to ensure compliance. Documentation in the chart should include that you have reviewed it and any pertinent information obtained from it (ICH 2019).

Prior to scheduling the patient for the first immunoglobulin infusion, planning as to the schedule for infusions needs to be considered. Immunoglobulin clinical trials enroll patients at specific infusion visit intervals that should be adhered to. Strategies for ensuring that infusions do not take place outside of the scheduled infusion interval include discussing planned vacations with the family prior to the first infusion, and scheduling infusions early in the infusion window so that if it needs to be rescheduled there is still time within the window to re-book. In addition, many clinical trials use central laboratories and consideration needs to be given to ordering supplies, statutory holidays, and shipper schedules when scheduling patients so that samples arrive in appropriate time frames (ICH 2019).

In preparation for the first infusion, subjects and parents should be reminded that good oral hydration is very important prior to immunoglobulin treatment, both for preventing reactions but also for assisting with intravenous insertion (Katz et al. 2007). We suggest that the child drink more the day prior to the infusion and continue for a day post infusion. Informing the family of fluid volumes and suggesting that they avoid caffeine-based drinks can ensure adequate hydration for the infusion.

Despite paediatric subjects in immunoglobulin trials having previous experience with other immunoglobulin products, the fact that this is something new can increase anxiety for both children and parents. In preparing children for the infusions, anxiety can be reduced by encouraging them to bring along activities they enjoy, and avoiding waiting times between arrival and start of procedures (Salmon 2006).

The procedure environment for needle insertions can also help reduce anxiety in children. Giving the child the choice of having parents in the room, whether to sit or lie down for needle insertions, and speaking directly to the child about what is going to happen can all reduce anxiety. Other strategies include allowing the child to have rituals around needle insertions such as a favourite toy, tourniquet, site, and utilizing distractions such as singing, counting, or bubbles for younger children, while older children may like to help by passing along blood tubes, or watching a video or listening to music (Salmon 2006).

For immunoglobulin studies, considerations around the needle insertion location should take into account the child’s planned activities during the infusion i.e., children playing games may prefer to have IV’s inserted higher up the arm. The size of catheter should also be considered. We utilize smaller needles of 22 gauge for most children, and 24 gauge for infants. It is important to ensure that the site is well secured once inserted to reduce the risk of infiltration and need for multiple insertions.

Many immunoglobulin studies involve pharmacokinetic analysis (PK) and children can be successfully enrolled if willing to participate. Strategies to reduce the number of blood draws and make the analysis easier on the child and family include leaving the IV in for up to 72 hours post infusion for subsequent early PK blood draws, if the study allows utilization of local laboratories or home care for blood draws. These agencies should also be provided with recommendations as to the needle size for children. If possible, try to arrange consistent providers for the blood draws so that the child is familiar with the provider, as this may reduce anxiety (Salmon 2006).

For immunodeficient patients who require immunoglobulin treatment for life, it is important that the care provided during trials does not negatively impact the child’s view towards ongoing immunoglobulin treatment. Adopting child-friendly strategies can make clinical immunoglobulin trials more tolerable for children and lead to successful completion of the trial. As well for successful outcomes, it is important to utilize strategies for clear documentation at every step of the research process, to allow for monitoring during the study, and audits post study for licensing of the investigational product.