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
v/cber/guidelines.htm.
For questions on the content of this guidance, contact the Division of Vaccines and Related Products Applications, Office of Vaccines Rearch and Review at 301-827-3070.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Rearch
September 2007
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)
磁砖十大品牌Guidance for Industry
Toxicity Grading Scale for Healthy Adult and Adolescent
Volunteers Enrolled in Preventive Vaccine Clinical Trials
赞赏造句This guidance reprents 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 u 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 dia in a healthy population. The Office of Vaccines Rearch and Review, Center for Biologics Evaluation and Rearch, regulates preventive vaccines under authority of ction 351 of the Public Health Service Act (42 U.S.C. 262), as well as specific ctions of the Federal Food, Drug, and Cosmetic Act, and reviews investigational new drug applications (INDs) and biologics licen 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 phas of vaccine testi
ng. The enrollment of healthy volunteers warrants a very low tolerance for risk in tho clinical trials.
This guidance provides you, sponsors, monitors, and investigators of vaccine trials, with recommendations on asssing the verity 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 uful in defining a particular study’s stopping rules (e.g., a certain number of adver events, as defined in the table, may call for stopping the study). Less extreme obrvations (e.g., mild) may not require discontinuing the study vaccine but can still contribute to evaluating safety by identifying parameters to focus upon in subquent 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 lecting the asssment criteria to be ud in a clinical trial of a preventive vaccine. We recommend incorporation of such appropriate, uniform, criteria into the investigational plan, ca 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 u of the word should in FDA’s guidances means that something is suggested or recommended, but not required.
II. BACKGROUND
Standardized toxicity asssment scales have been widely ud to evaluate products treating specific dias. For example, the National Cancer Institute’s Common Toxicity Criteria Scale and the Division of AIDS’ Toxicity Grading Scale standardize the evaluation of adver events among patients with cancer and HIV/AIDS, respectively (Refs. 1, 2). The defined toxicity parameters in tho scales are designed for patients who may already experience mild, moderate, or vere adver clinical or laboratory events due to the dia process, and may not be appropriate for healthy volunteers.
In the development of the toxicity grading scales for healthy volunteers, we cho parameter limit values bad on published information, when such values were available (Refs. 1-6). For example, t
he Brighton Collaboration has developed ca definitions and guidelines to evaluate some adver events associated with administering vaccines (Ref. 3). In some cas, parameter limit values were bad 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 exerci of clinical judgment, for example, consideration of the potential for ethnic differences in white blood cell (WBC) counts or gender differences in creatine phosphokina (CPK) values.
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III. TOXICITY
GRADING SCALE TABLES
Adver 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 u of a toxicity grading scale for adver events would not replace th
e regulatory requirements, using a scale to categorize adver events obrved 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.
家和万事兴歌词The 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 bad on one or more of the following: safety signals obrved in pre-clinical toxicology studies, the biological plausibility of the occurrence of certain adver events, or previous experience with a similar licend product.
As discusd above, the tables do not reprent a recommendation to monitor all the listed parameters in all clinical trials of healthy volunteers, nor do the tables reprent all possible parameters to be monitored. In addition, the tables do not reprent study inclusion or exclusion c
riteria. 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 Injectable Product Mild (Grade 1) Moderate(Grade 2) Severe (Grade 3) Potentially Life
Threatening
(Grade 4)
Pain Does not interfere
with activity Repeated u of non-
narcotic pain reliever
> 24 hours or
interferes with
activity
Any u of
narcotic pain
reliever or
prevents daily
activity
一次性袜子Emergency room
助教英文(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湘菜大全
Induration/Swelling ** 2.5 – 5 cm and
防护工程does not interfere
with activity 5.1 – 10 cm or
interferes with
activity
> 10 cm or
prevents daily
activity
Necrosis
recorded as a continuous variable.
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.
