Guideline No. 16
Freedom Of Information Summary Guidelines
Revised May 10, 1985
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE
Prepared by
Office of New Animal Drug Evaluation Center for Veterinary Medicine
Food and Drug Administration
Table of Contents
1. NADAs
2. Supplements
a. Pivotal Studies
b. Corroborative Studies
a. Pivotal Studies
b. Corroborative Studies
a. Drugs for Use in Food Animals
b. Antimicrobial Drugs Intended for Long Term, Subtherapeutic use in Animal Feeds
c. Drugs for Use in Non-Food Animals
d. Human Safety Considerations Other Than Food Safety
a. Supplemental Policy
b. Threshold Assessment
c."Pipeline Policy".
d. Combination Drugs for Food Animals
e.Generic Approvals
f. Rx/OTC Status
g. Other
FREEDOM OF INFORMATION SUMMARY GUIDELINES
The Freedom of Information (FOI) Summary Guidelines are designed to assist New Animal Drug Application (NADA) sponsors in preparing an "FOI Summary" and to assist the Center For Veterinary Medicine (CVM) in reviewing the Summaries and preparing the Agency Conclusions sections.
When approval of an original or supplemental NADA is published in the Federal Register, a summary of the safety and effectiveness information submitted to support the . approval of the application is publicly released by the Food and Drug Administration (FDA) in accordance with 21CFR section 514.11(e). This regulation states that CVM may prepare its own summary or may require the NADA sponsor to prepare one. The Center has elected to have the NADA sponsor prepare the summary.
Since the intent of the FOI Act is to inform the public at large, the FOI Summary must be written clearly and, as much as possible, in language that the average person can understand. However, this does not mean that scientific accuracy or detail should be sacrificed, nor does it preclude the use of medical or scientific terms.
The summary shall provide safety and effectiveness data and other information in sufficient detail to show the basis on which the agency approved the NADA or supplement. As shown in the outline below, greater detail is required for pivotal studies (those essential to a decision to approve) than for corroborative studies (those which form a portion of the basis for approval, but which are not, by themselves, essential to the decision to approve). Studies submitted, but not relied on (as either pivotal or corroborative).for the approval, need not be mentioned or described. However, the Summary shall describe the well-controlled studies on which approval was based including studies showing negative results. Results should be reported for all treatment groups, except those. not contributing pertinent information (positive or negative): to the label claims.
An omission or deviation in the "data package," from what is normally required for the type of drug being approved, should be noted and explained by the sponsor if the reason for the difference is based on science. If the difference is due to a policy decision or an applicable guideline, the agency will explain the reason(s) for the difference in the Agency Conclusions section.
In the outline below, the Center has attempted to cover each significant item that should be included in the Summary. Because of the dynamic nature of the approval process, however, it will be necessary to exercise judgment with respect to the presentation of data and information not specifically addressed by the outline, but which are significant in the approval of the application. In contrast, there will be circumstances in which it will be unproductive or unnecessary to provide all of the information listed in the outline. For example, if tests which were collateral to the objectives were conducted during trials the results need not be summarized in the detail needed for tests on which the drug's safety or effectiveness is being judged. The overriding guide, therefore, should be the intent of the Freedom of Information Act as applied to NADA approvals: to inform the public of the basis for the agency's approval of an NADA in language that a lay person can understand.
An exception to these general considerations is the use of published literature as a portion of the safety or effectiveness data. If a study forming a portion of the basis of approval is published in a generally available English language publication, the FOI summary need include only a citation and abstract. For studies published in a publication which is not readily available, or is in a foreign language, the F0I Summary should contain a detailed summary as described by these guidelines.
1. NADAs. 21 CFR 514.11(e) requires release of the FOI Summary after publication of an approval in the Federal Register. A Summary is required for all NADAs, including generic -(e.g., NAS/NRC) approvals and NADAs supported by reference to data in previously approved NADAs.
2. Supplements. An FOI Summary is required for each supplemental application that affects safety and/or effectiveness. The Summary need encompass only the data submitted with the supplement, unless review of data in the original NADA is required for approval of the supplement. In this case, except as provided by Section E, the Summary must encompass the data contained in the supplement and the safety and effectiveness data that was required to be reviewed from the original NADA.
If an application (NADA or supplement) requires a Summary, but a Summary has been previously prepared that the Center believes is adequate, cross-reference to the earlier Summary will be acceptable for applicable portions of the new Summary.
A summary may be inadequate because it is not clearly written in terms that an average person can understand, because it does not provide a sufficiently detailed summary of the safety and effectiveness data, or for other reasons. When an NADA sponsor submits a draft FOI Summary that the Center concludes is inadequate, the Center may revise the Summary or, more likely, the Center will advise the sponsor of the specific deficiencies and ask the sponsor to submit a revised summary.
The names of private owners of animals used in studies, to determine effectiveness, are ordinarily considered to be confidential and are not required to be included in the FOI summary. The same rule applies to individual identification of animals that could lead to identification of the owner, or that for some other reason would be subject to claims of confidentiality. An example of the latter is the name of a thoroughbred horse. Although data for individual animals are ordinarily not required in the FOI summary, when such data are appropriately presented care should be taken to avoid inadvertent identification of the owner.
Under-the FOI Act, trade secrets and confidential commercial information are exempt from disclosure. In addition, the' disclosure of trade secrets submitted to FDA is prohibited by 21 U.S.C. 331(j) and 18 U.S.C. 1905. Whether information is exempt from disclosure as a trade secret or confidential commercial information must be determined on a case-by-case
basis. The Center will use the following procedure to ensure that such information is not inadvertently released without a sponsor's knowledge:
a. The Center will assume that the sponsor waives any confidentiality objection with respect to material in the sponsor's draft, and to material added in a revised draft written by the sponsor at the Center's request.
b. If the Center makes substantive revisions to an FOI Summary, it will request the sponsor's concurrence in those revisions. If the sponsor does not concur, or if the Center asks the sponsor to include certain information and the sponsor declines to do so on the basis of confidentiality, a representative of the Center will consult verbally with the sponsor to attempt to resolve the dispute. The Center employee will prepare a memorandum summarizing such discussions.
c. If the dispute cannot be resolved on an informal basis, the sponsor must provide in writing a specific basis for its objection. The sponsor must adequately justify its objection to disclosure by providing specific reasons applicable to the particular information in question.
d. The Center may accept the sponsor's explanation. If it does not, the Center Director or Deputy Director, with the concurrence of the Office of General Counsel, will formally notify the sponsor in writing that the Center intends to include the disputed information and that, pursuant to 21CFR 20.46, the sponsor has five days in which to sue the agency to enjoin the disclosure. The letter will state why the Center does not agree with the sponsor's views.
e. If suit is initiated, the FOI Summary will consist of all undisputed information, together with a notation that litigation is pending to resolve the releasability of certain additional information.
The sponsor should submit, as part of the NADA or supplement, an original and three copies of the Summary, typed on plain white bond paper and unsigned.
The FOI Summary, together with the approved labeling and required environmental documents (e.g., an Environmental Impact Analysis Report, Environmental Assessment, or Environmental Impact Statement), will be placed on' public display with the Dockets Management Branch (HFA-305), Food and Drug Administration at the time the approval of the NADA is forwarded for publication in the Federal Register.
NADA Number:
Sponsor (name and address):
Generic Name:
Trade Name:
Marketing Status: Rx or OTC
Effect of Supplement: If the application is a supplement, include a concise statement explaining how the supplement modifies or changes the NADA.
2. Indications for Use: Indications ordinarily should be quoted verbatim from the labeling. If the description of the indications is lengthy, however, reference to the attached labeling is acceptable. Do not paraphrase.
3. Dosage Form(s), Route(s) of Administration, and Recommended Dosage(s):
This section of the Summary should discuss each adequate and well-controlled investigation separately, except that where data from two or more separate investigations are pooled for analytical purposes, either of the following may be applicable: (a) the results of the individual investigations and the pooled results should be summarized and statistical analysis of the pooled results should be reported, or (b), if the results of the investigations are not individually considered in the approval decision, the pooled results should be summarized and statistical-, analysis of the pooled results reported, but the results of the individual investigations need not be summarized. In case (b), however, the data will ordinarily be considered as constituting only one "adequate and well-controlled" study. Where the scientific and statistical justification for the pooling of data is not apparent from the description of the design of the study, a brief justification should be given.
The discussion should be descriptive and definitive, and the basis for conclusions should be explained.
a. Pivotal Studies (Pivotal studies are those essential to the decision to approve the NADA.) The following information should be provided for each pivotal study:
1) Identify the type of study. Examples:
a) Clinical (field) study.("Clinical" and "field" are used interchangeably in the FOI Summary Guidelines.)
b) Dose titration study.
c) Bioequivalency study.
d) Critical study (anthelmintics).
2) Name(s) and address(es) of investigator(s) who did the study.
3) General design of the investigation:
a) Purpose of study.
b) Test animals:
(1) Species and number per group.
(2) Identify appropriate subgroups (e.g., age, sex, weight, breed or class).
c) Type of control group used and explanations as needed.
(1) If a historical control is used, its use should be explained in terms of 514.111(a)(5)(ii)(a)(4)(iv). When animals are used as their own controls, the Summary should briefly explain why the use of the animals as their own controls is acceptable in terms of 514.111(a)(5)(ii)(a)(2)(iii) and explain which of the following treatments was administered, in the control phase, to animals designated as self control animals: no treatment, placebo treatment, or another drug (active treatment control).
(2) If active treatment control is used, and the control drug is a new animal drug that is not the subject of a currently approved NADA for the use in question, the reason why the drug is an appropriate control drug should be explained.
d) Diagnosis. Describe method(s) utilized.
e) Dosage form:
(1) Tablets, capsules, injectable, etc.
(2) If the formulation used in the study is not same as the formulation to be marketed, explain why its use is acceptable.
f) Route(s) of administration. If not the same as the product to be marketed, explain why its use is acceptable.
g) Dosage(s) used. If the "dose units of measurement" used in the study were not the same as those on the label, the "study dose units" should be converted to the label units and placed in parentheses immediately following the study dose units in the discussion of the study.
Example: "Dose in study was 11 mg/kg (5 mg/lb)."
h) Test duration.
i) Pertinent parameters measured. Examples:
(1) Clinical signs.
(2) Hematology.
(3) Blood chemistries.
(4) Cultures pre- and posttreatment.
(5) Histopathology.
(6) Weight gain/feed efficiency, etc.
4) Results. Present summary of data in tabular form, unless tables are not appropriate.
5) Statistical analysis.
a) Discussion of the statistical results should include-
(1) Identification of statistical method(s).
(2) A statement as to whether the differences (e.g., between test drug and control ) were considered to be statistically significant.
(3) If statistically significant, the level of confidence or "p" value.
b) If the data were not subjected to statistical analysis, the Summary should briefly explain why this was not necessary or appropriate.
c) If individual studies were combined for statistical analysis purposes, the combined statistical analyses should be presented.
6)Conclusion(s) drawn from the study.
7) Adverse reactions. If adverse reactions were encountered, they should be fully described. If no adverse reactions were observed, a statement to that effect should be included.
8) Special issues:
a) Waivers (The waiver provisions apply only to field investigations.) If, in accordance with the provisions of 514.111(a)(5)(ii)(a)(6), a waiver of any or all of the criteria defining "adequate and well-controlled investigations" in 514.111(a){5)(ii) is sought with respect to a specific clinical {field) investigation, a paragraph should be included stating:
(1) The specific provisions in the criteria from which the waiver is being sought.
(2) Why the criteria are not reasonably applicable to the particular clinical investigation.
(3) What alternative procedures, if any, have been employed.
(4) Results of the investigation.
(5) The basis upon which it can be concluded that the clinical investigation has yielded substantial evidence of effectiveness.
(6) Citations of literature relied on to help support the waiver.
b) Combination drugs. If the application pertains to a combination drug, the Summary should explain how the product complies with the combination drug policy stated in 21CFR 514.1(b){8)(v) and the Center's combination drug guidelines. Deviations from significant provisions of the guidelines should be explained.
c) NAS/NRC drugs. If effectiveness is asserted on the basis of equivalence to a drug that was subject of a National Academy of Sciences/National Research Council review, any bioequivalence data presented should be summarized. The FOI Summary should cite pertinent regulations and Federal Register documents.
d) Bioequivalence. In addition to the information listed in section a, Pivotal Studies, the following information should be presented.
(1) Serum level studies:
(a) Reference drug. If original reference drug is unavailable, state basis for selecting reference drug used.
(b) Give washout time between initial drug administration and crossover.
(2) Clinical studies (Used under clinical (field) conditions when drug cannot appropriately be measured in the blood or urine. Examples: topicals, anthelmintics, enteric antibiotics. not absorbed, etc.)
(a) Test animals
[1]Describe method of assignment of animals to the treatment groups.
[2] Indicate the total number of animals treated in each group and the number found acceptable.
[3] State parameters utilized in determining that the animals
had the condition(s) for which the drug is indicated in the labeling.
b. Corroborative Studies (Corroborative studies are those which form a portion of the basis for approval, but which are not essential by themselves to NADA approval.) Descriptions of these studies need not be as detailed as the summaries of the pivotal studies. At a minimum, the information listed in 1) - 4) and 6) below should be included. The information in No. 5), if any, should report those aspects of the study that are particularly pertinent to the reason(s) why the study is offered as corroborative support.
1) Name(s) and address(es) of the investigator(s) who conducted the study.
2) Animal species used and number per group.
3) Whether or not the study was well controlled and, if so, the type of control used.
4) Dosage(s) used and route(s) of administration. See a 3)(f) and (g).
5) Other information as appropriate.
6) Results and conclusion(s) drawn from the study.
a. Pivotal Studies.Each study should be discussed separately. The following should be provided for each study:
1) Identify the type of study. Examples:
a) Acute toxicity.
b) Subacute toxicity.
c) Chronic toxicity.
d) Reproductive, etc.
2) Name(s} and address(es) of investigator(s) who did the study.
3) General design of the study:
a) Purpose of study.
b) Test animals:
(1) Species and number per group.
(2) Identify appropriate subgroups (e.g., age, sex, weight, breed or class).
c) Dosage form:
(1) Tablets, capsules, injectable, etc.
(2) If the formulation used in the study is not the same as the formulation to be marketed, explain why its use is acceptable.
d) Dosage(s) used. See a 3) (g).
e) Route(s) of administration.
f) Test duration.
g) Pertinent parameters measured. Examples:
(1) Clinical signs.
(2) Hematology.
(3) Blood chemistries.
(4) Cultures pre- and post-treatment.
(5) Histopathology, etc.
4) Results. Show results of study in tabular form, unless not appropriate.
5) Statistical analysis, where appropriate.
6) Conclusion(s) drawn from the study.
b. Corroborative Studies. Descriptions of the studies need not be as detailed as the summaries of the pivotal studies. At a minimum, the information listed in 1) -5) and 7) below should be included. The information in No. 6), if any, should report those aspects of the study that are particularly pertinent to the reason(s) why the study is offered as corroborative support.
1) Type of study.
2) Name(s) and address(es) of investigator{s) who did the study.
3) Animal species used and number per group.
4) Whether or not the study was well controlled and, if so, the type of control used.
5) Dosage(s) used and routes of administration. See a 3)if) and (g).
6) Other information as appropriate.
7) Results and conclusion(s) drawn from the study.
a. Drugs for Use in Food Animals:
1) Toxicity tests:
a) Title.
b) Report number.
c) Starting date.
d) Termination date.
e) Name(s) and address(es) of investigator(s) who did the study.
f) Name and address of laboratory where study was done.
g) Identity of substance and dosage form tested.
h) Species and strain of test animal used.
i) Number of animals of each sex in each group.
j) Levels and duration of dosing.
k) Route of drug administration.
l) Parameters studied.
m) Significant toxicities observed.
n) No-observed-effect level.
o) Statistical analysis, where appropriate.
p) Conclusion(s) drawn from the study.
2) Safe concentration of total residue.
a) State the no-observed-effect level from the most sensitive study in the most sensitive species and the safety factor applied in calculating a safe concentration of total residue in edible tissue. State the appropriate factor used to adjust for consumption along with the safe concentration in each tissue.
b) When applicable, state the safe concentration of total residue derived from a Threshold . Assessment {TA).
c) When applicable, state the safe concentration of total residue derived from the Agency's risk assessment procedures.
3) Total Residue Depletion and Metabolism Studies
a) Name(s) and address(es) of investigator(s) who did the study.
b) Any appropriate descriptions of the animals used in the study (e.g. number of animals, age, sex, weight, breed or class).
c) Route of drug administration.
d) Time and duration of dosing.
e) Particular radioisotope used in the study.
f) Present in tabular form a summary of the average total residue concentration and its standard deviation in tissue at various withdrawal times. Data for individual animals should not be given.
g) Present a summary of metabolism studies leading to identification of major metabolites in the target species and in the test species.
4) Tolerance for the marker residue
This section should contain a summary of the basis for selecting the target tissue, the marker residue, and the required sensitivity for the regulatory method of analysis (Rm or tolerance). The tolerance refers to the concentration of marker residue in the target tissue selected to monitor for the total residue of the drug in the treated animal.
If the approval is one which requires the submission of data to show the effect of the long-term use on development of antibiotic resistance and on the Salmonella reservoir in the target species, in accordance with 21 CFR 558.15, then such data should be summarized here.
Discuss hazards or characteristics of drug pertinent to possession, handling, administration, and relevant aspects of labeling, marketing, packaging, etc.
This section of the Summary will contain a discussion of policy considerations involved in the approval of the subject drug. The following examples will serve to illustrate the type of information and the format that will be followed.
If the subject NADA is a supplement to an existing application, this section should cite the agency's supplemental approval policy (42 FR 64367, December 23, 1977), and should explain the basis for assignment of the NADA to a particular category.
If the procedures described in the Threshold Assessment Guideline were used to determine whether chronic bioassays were needed, a summary of the process should be provided in this section. The initial and final category into which a drug was placed should be described and explained.
If the approved drug was excused from satisfying certain data requirements (See 48 FR 6361, February 11, 1983 (the "Pipeline Policy")), a discussion should be presented on how the drug was shown to meet each of the four criteria that must be met to be within the scope of the Pipeline Policy.
If the NADA is for a combination of previously approved drugs, this section should contain a statement that each drug in the combination has depleted to its safe concentration by the proposed withdrawal time and that the drugs in the combination do not interfere with the regulatory assays for each drug.
If the subject NADA is approvable under the Agency's guidelines and procedures for evaluating generic equivalent applications, the basis for this classification should be stated.
This section is applicable to all original NADAs (except DESI NADAs), and to all supplements for a new species or requesting change in the Rx/OTC status.
This section will include a brief statement explaining why a drug is to be categorized as either Rx or OTC. The explanation should not be comprised exclusively of a conclusion, e.g., "adequate directions can/cannot be written." If a product is to be Rx, this section should list each substantial reason why adequate directions for laymen's use cannot be written. If the drug is to be OTC, explanations given should anticipate any substantial question that might be raised as to why the product is categorized as OTC, e.g., why a layman may be able to diagnose a particular condition that appears to be one that ordinarily requires professional intervention. Refer to Guide 1240.2220, CVM Policy and Procedures Manual.
Attachments. A copy of the approved label and labeling will be attached to the Summary by Center personnel.
|
||||||
 |
||||||
|
||||||