Guidance for Industry
 
 
Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine 
Clinical Trials
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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  Contains Nonbinding Recommendations 
 
 
Table of Contents 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  TOXICITY GRADING SCALE TABLES.....................................................................2 
A.  Tables for Clinical Abnormalities.......................................................................3 
B.  Tables for Laboratory Abnormalities.................................................................6 
IV.  REFERENCES..................................................................................................................8 
i  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 Administrations (FDAs) 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. 
 
 
I.  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 studys 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). 
 
1  Contains Nonbinding Recommendations 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe FDAs 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 FDAs guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND 
 
Standardized toxicity assessment scales have been widely used to evaluate products treating 
specific diseases.  For example, the National Cancer Institutes 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. 
 
 
III.  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 
2  Contains Nonbinding Recommendations 
 
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. 
 
A.  Tables for Clinical Abnormalities 
 
Local Reaction to  Mild (Grade 1)  Moderate(Grade 2)  Severe (Grade 3)  Potentially Life 
Injectable Product  Threatening 
(Grade 4) 
Pain  Does not interfere  Repeated use of non- Any use of  Emergency room 
with activity  narcotic pain reliever  narcotic pain  (ER) visit or 
> 24 hours or  reliever or  hospitalization 
interferes with  prevents daily 
activity    activity  
Tenderness  Mild discomfort to  Discomfort with  Significant  ER visit or 
touch  movement  discomfort at rest  hospitalization 
Erythema/Redness *  2.5  5 cm  5.1  10 cm  > 10 cm  Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling **  2.5  5 cm and  5.1  10 cm or  > 10 cm or  Necrosis 
does not interfere  interferes with  prevents daily 
with activity  activity  activity 
*  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. 
3  Contains Nonbinding Recommendations 
 
 
Vital Signs *  Mild (Grade 1)  Moderate(Grade 2)  Severe (Grade 3)  Potentially Life 
Threatening 
(Grade 4) 
Fever (C) **  38.0  38.4  38.5  38.9  39.0  40  > 40 
          (F) **  100.4  101.1  101.2  102.0  102.1  104  > 104 
Tachycardia - beats per  101  115  116  130  > 130  ER visit or 
minute  hospitalization for 
arrhythmia 
Bradycardia - beats per  50  54  45  49  < 45  ER visit or 
minute***   hospitalization for 
arrhythmia 
Hypertension (systolic) -  141  150  151  155  > 155  ER visit or 
mm Hg  hospitalization for 
malignant 
hypertension 
Hypertension (diastolic) -   91  95  96  100  > 100  ER visit or 
mm Hg  hospitalization for 
malignant 
hypertension 
Hypotension (systolic)   85  89  80  84  < 80  ER visit or 
mm Hg  hospitalization for 
hypotensive shock 
Respiratory Rate  breaths  17  20  21  25  > 25  Intubation 
per minute 
*  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  Some interference  Prevents daily  ER visit or 
with activity or 1  2 with activity or > 2  activity, requires  hospitalization for 
episodes/24 hours  episodes/24 hours   outpatient IV  hypotensive shock 
hydration 
Diarrhea  2  3 loose stools or 4  5 stools or  6 or more watery  ER visit or 
< 400 gms/24 hours 400  800 gms/24  stools or  hospitalization 
hours  > 800gms/24 hours 
or requires 
outpatient IV 
hydration 
Headache  No interference with Repeated use of non-  Significant; any  ER visit or 
activity  narcotic pain  use of narcotic  hospitalization 
reliever > 24 hours or pain reliever or 
some interference  prevents daily 
with activity   activity  
Fatigue  No interference with Some interference  Significant;  ER visit or 
activity  with activity  prevents daily  hospitalization 
activity 
Myalgia  No interference with Some interference  Significant;  ER visit or 
activity  with activity  prevents daily  hospitalization 
activity 
4  Contains Nonbinding Recommendations 
 
 
Systemic Illnes  Mild (Grade 1)  (Moderate(Grade 2) Severe (Grade 3)  Potentially Life 
Threatening 
(Grade 4) 
Illness or clinical adverse  No interference with Some interference  Prevents daily  ER visit or 
event (as defined  activity  with activity not  activity and  hospitalization 
according to applicable  requiring medical  requires medical 
regulations)  intervention  intervention 
 
5  Contains Nonbinding Recommendations 
 
B.  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  Severe  Potentially Life 
(Grade 2)  (Grade 3)  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        Insulin 
Fasting  mg/dL  100  110  111  125  >125  requirements or 
Random  mg/dL  110  125  126  200  >200  hyperosmolar 
coma 
Blood Urea Nitrogen  23  26  27  31  > 31  Requires 
BUN mg/dL  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  2.3  2.5  2.0  2.2  1.6  1.9  < 1.6  
mg/dL 
CPK  mg/dL  1.25  1.5 x  1.6  3.0 x ULN  3.1 10 x ULN  > 10 x ULN 
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   1.1  2.0 x ULN  2.1  3.0 x ULN  3.1  10  x ULN  > 10 x ULN 
increase by factor 
Liver Function Tests ALT, AST  1.1  2.5 x ULN  2.6  5.0 x ULN  5.1  10 x ULN  > 10 x ULN 
increase by factor 
Bilirubin  when accompanied  1.1  1.25 x ULN  1.26  1.5 x ULN  1.51  1.75 x ULN  > 1.75 x ULN 
by any increase in Liver Function Test 
increase by factor 
Bilirubin  when Liver Function Test  1.1  1.5 x ULN  1.6  2.0 x ULN  2.0  3.0 x ULN  > 3.0 x ULN 
is normal; increase by factor 
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. 
6  Contains Nonbinding Recommendations 
 
 
Hematology *  Mild (Grade 1)  Moderate  Severe (Grade 3)  Potentially Life 
(Grade 2)  Threatening 
(Grade 4) 
Hemoglobin (Female) - gm/dL  11.0  12.0  9.5  10.9  8.0  9.4  < 8.0 
Hemoglobin (Female)  Any decrease  1.5  1.6  2.0  2.1  5.0  > 5.0 
change from baseline value -  gm/dL 
Hemoglobin (Male) - gm/dL  12.5  13.5  10.5  12.4  8.5  10.4  < 8.5 
Hemoglobin (Male)  Any decrease  1.5   1.6  2.0  2.1  5.0  > 5.0 
change from baseline value  gm/dL 
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  1.0  1.10 x  1.11  1.20 x ULN  1.21  1.25 x ULN  > 1.25 ULN 
(prothrombin time)  ULN** 
PTT  increase by factor  1.0  1.2 x ULN  1.21  1.4 x ULN  1.41  1.5 x ULN  > 1.5 x ULN 
(partial thromboplastin time) 
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  Severe (Grade 3)  Potentially Life 
(Grade 2)  Threatening 
(Grade 4) 
Protein  Trace  1+  2+  Hospitalization or 
dialysis 
Glucose  Trace  1+  2+  Hospitalization for 
hyperglycemia 
Blood (microscopic)   1 - 10  11  50  > 50 and/or gross  Hospitalization or 
red blood cells per  blood  packed red blood 
high power field (rbc/hpf)  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. 
7  Contains Nonbinding Recommendations 
 
IV.  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/DAIDSAEGra
dingTable.pdf) 
 
6.  Kratz A, Ferraro M, Sluss PM, Lewandrowski KB.  Laboratory Reference Values.  New 
England Journal of Medicine.  2004;351:1548-1563. 
8