Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials

Name: Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials


Status of Guidance: Final Guidance

Guidance Released: September 2007

Link to Guidance:
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm074775.htm#TableofContents

Target Audience: Sponsors (eg, pharmaceutical companies), monitors (eg, clinical research associates), investigators (eg, research physicians), and Institutional Review Boards (IRBs) of vaccine trials

Laws and Regulations Referenced:
1. Section 351 of the Public Health Service Act (42 U.S.C. 262) by which the Office
of Vaccines Research and Review, Center for Biologics Evaluation and Research,
regulates preventive vaccines
2. The Federal Food, Drug, and Cosmetic Act, eg, Title 21 Code of Federal Regulations (CFR) Parts 312, 600, and 601, which address investigational new drug applications (INDs) and biologics license applications (BLAs)
3. 21 CFR 312.32, 312.33, 312.50, 312.55, 312.56, 312.60, 312.62, 312.64, and 312.66 which present the regulations involved with the recording, monitoring, and reporting of adverse events (AEs) in clinical trials

Summary: The Office of Vaccines Research and Review (of the Center for Biologics Evaluation and Research [CBER] of the Food and Drug Administration [FDA] of the US Department of Health and Human Services [HHS]) follows established rules to control the study of preventive vaccines. Preventive vaccines are most often developed to prevent disease in healthy people. When healthy people are enrolled in clinical trials, there is a very low tolerance for risk of AEs for the volunteer. The vaccine’s benefits should greatly outweigh its risks of harming a healthy volunteer.

To consistently evaluate the risk of AEs that healthy adult and adolescent volunteers undergo in preventive vaccine clinical trials, recommendations for the assessment of the severity of clinical and laboratory abnormalities are presented. The authors of this guidance recommend that these appropriate and uniform criteria be incorporated into the vaccine’s investigational plan (study protocol), case report forms, and study reports. That said, they also recommend that the clinical and laboratory parameters being monitored be tailored to the needs of each study vaccine. By this they mean that additional parameters might be added in a clinical study of a vaccine based on one or more of the following: safety signals detected in pre-clinical toxicology studies, the theoretical possibility of the occurrence of certain AEs, or prior experience with a similar licensed vaccine.

Rationale: If all sponsors of vaccine trials use uniform criteria for categorizing toxicities in healthy volunteers, comparisons of safety data among groups within the same study and also between different studies will be improved.

Resulting Recommendations: The following criteria should be assessed in all preventive vaccine clinical trials conducted in healthy adult and adolescent volunteers:

· Clinical: vital signs, local (injection site) reactions, and general (systemic) reactions
· Laboratory: results of serum chemistry assays, whole blood hematology tests, and urinalysis

When these criteria are outside of the normal range of results, they should be graded either Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3) or Potentially Life Threatening (Grade 4) according to the measurements listed in the Tables for Clinical Abnormalities and Tables for Laboratory Abnormalities of the guidance.

Impact: The use of uniform AE/toxicity criteria to evaluate the safety of vaccines in healthy volunteers will enhance our current understanding of immunization safety by improving the comparability of vaccine safety data. If this guidance is followed, many will benefit, not least of which are the current and future vaccinees. Additionally, scientists, health officials, and healthcare providers who need to make scientifically sound decisions and who need to obtain, interpret, provide, and report information on immunization safety will benefit.

My comments:
Many vaccines are administered to neonates, infants, toddlers, and children. This guidance would become complete if it also addressed toxicity grading scales for these patient populations.

The addition of language describing Serious Adverse Events (SAEs) and providing a distinction from severe AEs would also be helpful. It is not clear to me whether the Grade 4 (Potentially Life Threatening) category would be equivalent to an SAE.