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

[PDF Printable Version - 183 KB]

Additional copies of this guidance are available from the Office of Communication, Training and Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at http://www.fda.gov/cber/guidelines.htm.

For questions on the content of this guidance, contact the Division of Vaccines and Related Products Applications, Office of Vaccines Research and Review at 301-827-3070.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
September 2007


Table of Contents
  1. INTRODUCTION
  2. BACKGROUND
  3. TOXICITY GRADING SCALE TABLES

    1. Tables for Clinical Abnormalities
    2. Tables for Laboratory Abnormalities
  4. REFERENCES

Contains Nonbinding Recommendations

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

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
  1. INTRODUCTION

Preventive vaccines are usually developed to prevent disease in a healthy population. The Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, regulates preventive vaccines under authority of section 351 of the Public Health Service Act (42 U.S.C. 262), as well as specific sections of the Federal Food, Drug, and Cosmetic Act, and reviews investigational new drug applications (INDs) and biologics license applications (BLAs). (See, for example, Title 21 Code of Federal Regulations (CFR) Parts 312, 600, and 601). Most of the clinical trials of preventive vaccines conducted to support INDs and BLAs enroll healthy volunteers in all phases of vaccine testing. The enrollment of healthy volunteers warrants a very low tolerance for risk in those clinical trials.

This guidance provides you, sponsors, monitors, and investigators of vaccine trials, with recommendations on assessing the severity of clinical and laboratory abnormalities in healthy adult and adolescent volunteers enrolled in clinical trials. The grading system described in the table can also be useful in defining a particular study's stopping rules (e.g., a certain number of adverse events, as defined in the table, may call for stopping the study). Less extreme observations (e.g., mild) may not require discontinuing the study vaccine but can still contribute to evaluating safety by identifying parameters to focus upon in subsequent product development. Uniform criteria for categorizing toxicities in healthy volunteers can improve comparisons of safety data among groups within the same study and also between different studies. We, FDA, recommend using toxicity grading scale tables, provided below, as a guideline for selecting the assessment criteria to be used in a clinical trial of a preventive vaccine. We recommend incorporation of such appropriate, uniform, criteria into the investigational plan, case report forms, and study reports and correspondence with FDA, sponsors, monitors, investigators, and IRBs.

This guidance finalizes the draft guidance of the same title dated April 2005 (70 FR 22664, May 2, 2005).

FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe FDA's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA's guidances means that something is suggested or recommended, but not required.

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  1. BACKGROUND

Standardized toxicity assessment scales have been widely used to evaluate products treating specific diseases. For example, the National Cancer Institute's Common Toxicity Criteria Scale and the Division of AIDS' Toxicity Grading Scale standardize the evaluation of adverse events among patients with cancer and HIV/AIDS, respectively (Refs. 1, 2). The defined toxicity parameters in those scales are designed for patients who may already experience mild, moderate, or severe adverse clinical or laboratory events due to the disease process, and may not be appropriate for healthy volunteers.

In the development of the toxicity grading scales for healthy volunteers, we chose parameter limit values based on published information, when such values were available (Refs. 1-6). For example, the Brighton Collaboration has developed case definitions and guidelines to evaluate some adverse events associated with administering vaccines (Ref. 3). In some cases, parameter limit values were based on clinical experience and experience reviewing vaccine clinical trials that enroll normal healthy subjects.

Toxicity grading scales for laboratory abnormalities should consider the local laboratory reference values when the parameter limit values are defined. The characterization of laboratory parameters among some populations of healthy adults and adolescents may require the exercise of clinical judgment, for example, consideration of the potential for ethnic differences in white blood cell (WBC) counts or gender differences in creatine phosphokinase (CPK) values.

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  1. TOXICITY GRADING SCALE TABLES

Adverse events in a clinical trial of an investigational vaccine must be recorded and monitored and, when appropriate, reported to FDA and others involved in an investigation (sponsors, IRBs, and investigators). (See, for example, 21 CFR 312.32, 312.33, 312.50, 312.55, 312.56, 312.60, 312.62, 312.64, 312.66). Although the use of a toxicity grading scale for adverse events would not replace these regulatory requirements, using a scale to categorize adverse events observed during a clinical trial may assist you in monitoring safety and making required reports. Nonetheless, we believe that categorization or grading of data as outlined in this document is supplementary to and should not replace full and complete data analysis.

These guidelines for toxicity grading scales are primarily intended for healthy adult and adolescent volunteers. The parameters in the tables below are not necessarily applicable to every clinical trial of healthy volunteers. The parameters monitored should be appropriate for the specific study vaccine. For some preventive vaccines under development, it may be appropriate to include additional parameters to be monitored during a clinical trial or to alter the choice of values in the toxicity table. For example, additional parameters might be added based on one or more of the following: safety signals observed in pre-clinical toxicology studies, the biological plausibility of the occurrence of certain adverse events, or previous experience with a similar licensed product.

As discussed above, the tables do not represent a recommendation to monitor all the listed parameters in all clinical trials of healthy volunteers, nor do the tables represent all possible parameters to be monitored. In addition, these tables do not represent study inclusion or exclusion criteria. We recommend that the parameters monitored be appropriate for the study vaccine administered to healthy volunteers participating in the clinical trial.

  1. Tables for Clinical Abnormalities
    Local Reaction to Injectable Product Mild
    (Grade 1)
    Moderate
    (Grade 2)
    Severe
    (Grade 3)
    Potentially Life Threatening (Grade 4)
    Pain Does not interfere with activity Repeated use of non-narcotic pain reliever > 24 hours or interferes with activity Any use of narcotic pain reliever or prevents daily activity Emergency room (ER) visit or hospitalization
    Tenderness Mild discomfort to touch Discomfort with movement Significant discomfort at rest ER visit or hospitalization
    Erythema/Redness * 2.5 - 5 cm 5.1 - 10 cm > 10 cm Necrosis or exfoliative dermatitis
    Induration/Swelling ** 2.5 - 5 cm and does not interfere with activity 5.1 - 10 cm or interferes with activity > 10 cm or prevents daily activity Necrosis
    * In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a continuous variable.
    ** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.
    Vital Signs * Mild
    (Grade 1)
    Moderate
    (Grade 2)
    Severe
    (Grade 3)
    Potentially Life Threatening
    (Grade 4)
    Fever (°C) **
               (°F) *
    38.0 – 38.4
    100.4 – 101.1
    38.5 – 38.9
    101.2 – 102.0
    39.0 – 40
    102.1 – 104
    > 40
    > 104
    Tachycardia - beats per minute 101 – 115 116 – 130 > 130 ER visit or hospitalization for arrhythmia
    Bradycardia - beats per minute*** 50 – 54 45 – 49 < 45 ER visit or hospitalization for arrhythmia
    Hypertension (systolic) - mm Hg 141 – 150 151 – 155 > 155 ER visit or hospitalization for malignant hypertension
    Hypertension (diastolic) - mm Hg 91 – 95 96 – 100 > 100 ER visit or hospitalization for malignant hypertension
    Hypotension (systolic) – mm Hg 85 – 89 80 – 84 < 80 ER visit or hospitalization for hypotensive shock
    Respiratory Rate – breaths per minute 17 – 20 21 – 25 > 25 Intubation
    * Subject should be at rest for all vital sign measurements.
    ** Oral temperature; no recent hot or cold beverages or smoking.
    *** When resting heart rate is between 60 - 100 beats per minute. Use clinical judgement when characterizing bradycardia among some healthy subject populations, for example, conditioned athletes.
    Systemic
    (General)
    Mild
    (Grade 1)
    Moderate
    (Grade 2)
    Severe
    (Grade 3)
    Potentially Life Threatening (Grade 4)
    Nausea/vomiting No interference with activity or 1 - 2 episodes/24 hours Some interference with activity or > 2 episodes/24 hours Prevents daily activity, requires outpatient IV hydration ER visit or hospitalization for hypotensive shock
    Diarrhea 2 - 3 loose stools or < 400 gms/24 hours 4 - 5 stools or 400 - 800 gms/24 hours 6 or more watery stools or > 800gms/24 hours or requires outpatient IV hydration ER visit or hospitalization
    Headache No interference with activity Repeated use of non-narcotic pain reliever > 24 hours or some interference with activity Significant; any use of narcotic pain reliever or prevents daily activity ER visit or hospitalization
    Fatigue No interference with activity Some interference with activity Significant; prevents daily activity ER visit or hospitalization
    Myalgia No interference with activity Some interference with activity Significant; prevents daily activity ER visit or hospitalization
    Systemic Illnes Mild
    (Grade 1)
    Moderate
    (Grade 2)
    Severe
    (Grade 3)
    Potentially Life Threatening (Grade 4)
    Illness or clinical adverse event (as defined according to applicable regulations) No interference with activity Some interference with activity not requiring medical intervention Prevents daily activity and requires medical intervention ER visit or hospitalization
  2. Tables for Laboratory Abnormalities

    The laboratory values provided in the tables below serve as guidelines and are dependent upon institutional normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.

    Serum * Mild
    (Grade 1)
    Moderate
    (Grade 2)
    Severe
    (Grade 3)
    Potentially Life Threatening
    (Grade 4)**
    Sodium – Hyponatremia mEq/L 132 – 134 130 – 131 125 – 129 < 125
    Sodium – Hypernatremia mEq/L 144 – 145 146 – 147 148 – 150 > 150
    Potassium – Hyperkalemia mEq/L 5.1 – 5.2 5.3 – 5.4 5.5 – 5.6 > 5.6
    Potassium – Hypokalemia mEq/L 3.5 – 3.6 3.3 – 3.4 3.1 – 3.2 < 3.1
    Glucose – Hypoglycemia mg/dL 65 – 69 55 – 64 45 – 54 < 45
    Glucose – Hyperglycemia
    Fasting – mg/dL
    Random – mg/dL
     
    100 – 110
    110 – 125
     
    111 – 125
    126 – 200
     
    >125
    >200
    Insulin requirements or hyperosmolar coma
    Blood Urea Nitrogen
    BUN mg/dL
    23-26 27 – 31 > 31 Requires dialysis
    Creatinine – mg/dL 1.5 – 1.7 1.8 – 2.0 2.1 – 2.5 > 2.5 or requires dialysis
    Calcium – hypocalcemia mg/dL 8.0 – 8.4 7.5 – 7.9 7.0 – 7.4 < 7.0
    Calcium – hypercalcemia mg/dL 10.5 – 11.0 11.1 – 11.5 11.6 – 12.0 > 12.0
    Magnesium – hypomagnesemia mg/dL 1.3 – 1.5 1.1 – 1.2 0.9 – 1.0 < 0.9
    Phosphorous – hypophosphatemia mg/dL 2.3 – 2.5 2.0 – 2.2 1.6 – 1.9 < 1.6
    CPK – mg/dL 1.25 – 1.5 x ULN*** 1.6 – 3.0 x ULN 3.1 –10 x ULN > 10 x ULN
    Albumin – Hypoalbuminemia g/dL 2.8 – 3.1 2.5 – 2.7 < 2.5 --
    Total Protein – Hypoproteinemia g/dL 5.5 – 6.0 5.0 – 5.4 < 5.0 --
    Alkaline phosphate – increase by factor 1.1 – 2.0 x ULN 2.1 – 3.0 x ULN 3.1 – 10 x ULN > 10 x ULN
    Liver Function Tests –ALT, AST increase by factor 1.1 – 2.5 x ULN 2.6 – 5.0 x ULN 5.1 – 10 x ULN > 10 x ULN
    Bilirubin – when accompanied by any increase in Liver Function Test increase by factor 1.1 – 1.25 x ULN 1.26 – 1.5 x ULN 1.51 – 1.75 x ULN > 1.75 x ULN
    Bilirubin – when Liver Function Test is normal; increase by factor 1.1 – 1.5 x ULN 1.6 – 2.0 x ULN 2.0 – 3.0 x ULN > 3.0 x ULN
    Cholesterol 201 – 210 211 – 225 > 226 ---
    Pancreatic enzymes – amylase, lipase 1.1 – 1.5 x ULN 1.6 – 2.0 x ULN 2.1 – 5.0 x ULN > 5.0 x ULN
    * The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
    ** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value that falls within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if the subject had a new seizure associated with the low sodium value.
    ***ULN" is the upper limit of the normal range.
    Hematology * Mild
    (Grade 1)
    Moderate
    (Grade 2)
    Severe
    (Grade 3)
    Potentially Life Threatening
    (Grade 4)
    Hemoglobin (Female) - gm/dL 11.0 – 12.0 9.5 – 10.9 8.0 – 9.4 < 8.0
    Hemoglobin (Female) change from baseline value - gm/dL Any decrease – 1.5 1.6 – 2.0 2.1 – 5.0 > 5.0
    Hemoglobin (Male) - gm/dL 12.5 – 13.5 10.5 – 12.4 8.5 – 10.4 < 8.5
    Hemoglobin (Male) change from baseline value – gm/dL Any decrease – 1.5 1.6 – 2.0 2.1 – 5.0 > 5.0
    WBC Increase - cell/mm3 10,800 – 15,000 15,001 – 20,000 20,001 – 25, 000 > 25,000
    WBC Decrease - cell/mm3 2,500 – 3,500 1,500 – 2,499 1,000 – 1,499 < 1,000
    Lymphocytes Decrease - cell/mm3 750 – 1,000 500 – 749 250 – 499 < 250
    Neutrophils Decrease - cell/mm3 1,500 – 2,000 1,000 – 1,499 500 – 999 < 500
    Eosinophils - cell/mm3 650 – 1500 1501 - 5000 > 5000 Hypereosinophilic
    Platelets Decreased - cell/mm3 125,000 – 140,000 100,000 – 124,000 25,000 – 99,000 < 25,000
    PT – increase by factor (prothrombin time) 1.0 – 1.10 x ULN** 1.11 – 1.20 x ULN 1.21 – 1.25 x ULN > 1.25 ULN
    PTT – increase by factor (partial thromboplastin time) 1.0 – 1.2 x ULN 1.21 – 1.4 x ULN 1.41 – 1.5 x ULN > 1.5 x ULN
    Fibrinogen increase - mg/dL 400 – 500 501 – 600 > 600 --
    Fibrinogen decrease - mg/dL 150 – 200 125 – 149 100 – 124 < 100 or associated with gross bleeding or disseminated intravascular coagulation (DIC)
    * The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
    ** "ULN" is the upper limit of the normal range.
    Urine * Mild
    (Grade 1)
    Moderate
    (Grade 2)
    Severe
    (Grade 3)
    Potentially Life Threatening
    (Grade 4)
    Protein Trace 1+ 2+ Hospitalization or dialysis
    Glucose Trace 1+ 2+ Hospitalization forhyperglycemia
    Blood (microscopic) - red blood cells per high power field (rbc/hpf) 1 - 10 11 - 50 > 50 and/or gross blood Hospitalization or packed red blood cells (PRBC) transfusion
    * The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.

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  1. REFERENCES 
  1. National Cancer Institute Common Toxicity Criteria, April 30, 1999. (http://ctep.cancer.gov/reporting/CTC-3.html)
  2. Division of AIDS Table for Grading Severity of Adult Adverse Experiences; August 1992. (http://rcc.tech-res-intl.com/tox_tables.htm)
  3. The Brighton Collaboration. Finalized Case Definitions and Guidelines. (http://brightoncollaboration.org/internet/en/index/definition___guidelines.html)
  4. HIV Vaccine Trials Network Table for Grading Severity of Adverse Experiences; September 18, 2002. (http://rcc.tech-res-intl.com/tox_tables.htm)
  5. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, December 2004. (http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/PDF/Safety/DAIDSAEGradingTable.pdf)
  6. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory Reference Values. New England Journal of Medicine. 2004;351:1548-1563.

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