The Merck working group drafted a revised VRC based on the FDA Guidance by aligning each section with the corresponding recommendations (). In the FDA Guidance, the toxicity grading recommendations are for investigators to assess severity of clinical abnormalities. The original validated VRC was completed by clinical trial subjects and provides clinical staff with the information needed to properly grade toxicity scores. The challenge was to adapt this guidance while maintaining as much of the original version as possible.
The FDA Guidance provides suggestions for severity assessment based on a 4-part grading scale, including Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3), and Potentially Life Threatening (Grade 4). This scale includes interference with activity level, use of narcotic pain reliever, size measurements of local reaction at the injection site, and/or whether urgent medical attention was required. The revised VRC incorporated components of these suggested severity assessments while retaining as much of the original validated VRC rating scale as possible. For example, the severity option in the FDA Guidance, “Potentially Life Threatening (Grade 4) – Emergency room (ER) visits or hospitalizations,” was excluded from the revised VRC because ER visits may not accurately reflect a life-threatening event, given the widely varied healthcare systems, especially in international trials. Therefore, events requiring use of urgent medical care is captured as a separate item on the revised VRC (not shown). In addition, the use of narcotic pain reliever was retained and is recorded on a separate page within the revised VRC to maintain consistency with the original, validated VRC.
The revised VRC was evaluated by two focus groups of participants who were unfamiliar with using the original VRC. Participants consisted of a convenience sample of Merck employees separated into two demographically similar groups. In addition, within each group, every attempt was made to recruit diverse subjects in terms of demographic characteristics such as age, gender, education, and ethnic background. The purpose of this effort was to gain feedback on the functionality, general understanding and user-friendliness of sections of the revised VRC (i.e., temperature, measurement, redness/swelling, pain/tenderness, severity, injection site reactions, instructions, etc.). At the beginning of each focus group, participants received a copy of the revised Adult/Adolescent VRC and were asked questions from the moderator, with a focus on three areas as specified below, based on a prepared script.
Measurements of Redness and Swelling
The original VRC used a ruler divided into 8 one-inch (~2.5cm) sections (labeled 1 to 8) to assist trial subjects in measuring the size of any redness or swelling observed after vaccination at the injection site1
(). Trial subjects were instructed to measure the size of the redness or swelling and mark the appropriate corresponding box. In order to adapt to the VRC to the FDA Guidance (), the ruler was redesigned into increments of five 2.5 cm sections, each labeled “A” through “E→.”
Severity of Redness and Swelling
To minimize revision to the original validated VRC, redness and swelling assessments were retained in their original format and did not include severity rating options for swelling as recommended in the FDA Guidance. Participants were instructed to review the content of the VRC and provide feedback on their understanding of the questions, response scale, instructions and if any areas needed to be revised.
Severity of Pain and Tenderness
Because the original development of the VRC revealed that subjects could not meaningfully distinguish pain and tenderness, the combined assessment, pain and tenderness was kept as a single item as in the original VRC, and not separated as the FDA guidance recommends. However, during focus groups, participants were specifically asked if they could distinguish between the two concepts.