define the study terms described in section 58.35 (b)(3) and section 58.105(d). For these sections, the traditional terms found in the toxicology literature may be used.

2. Must an analytical method be totally contained in the protocol?

No. The protocol must state the type and frequency of tests to be made. Type can be connoted by reference to literature citations or the SOPs as applicable.

3. Does each nonclinical laboratory study require a sponsor-approved specific protocol?

Yes. However, the laboratory that conducts the study can also qualify as the sponsor of the study.

4. Do unforeseen circumstances which occur during a study and which necessitate minor operational changes have to be reported as protocol amendments?

Unforeseen circumstances which have only a one time effect (different date of sample collection, animal weghings) need to be reported only in the raw data and the final report. However, such circumstances which result in a systematic change, e.g. in the SOPs or in the protocol, should also be made by a protocol amendment. The

protocol amendment need not be made in advance but should be made as rapidly as possible.

5. Pathologists at a firm would like to take tissues from animals in a nonclinical study which would be used to conduct exploratory research studies. The tissues would not be part of the nonclinical laboratory study design and the results would not necessarily pertain to the study objectives. What would the GLPs require in this case?

The protocol should state that tissues are to be taken from the experimental animals and that the tissues would be used for exploratory research purposes. If any effects were observed in the exploratory research studies which would influence the

interpretation of the results of the nonclinical laboratory study, these effects must be reported in the final report.

6. Does the protocol have to list the SOPs used in a specific study?

The protocol must list the type and frequency of tests, analyses, and measurements to be made in the study. Where these are covered by SOPs, they should be listed in the protocol.

7. Do the GLPs require that absorption studies be done on each test article?

No. The GLPs require that, if absorption studies are needed to achieve the scientific objectives of the study plan, the protocol should describe the methods to be used to determine absorption. Whether or not absorption studies are required is a scientific issue to be decided by the study scientists.

8. Who assesses protocol validity (No. of animals, test article dosage, test system, etc.)?

This is done by the study scientists using the scientific literature, published guidelines, advice from regulatory agencies, and prior experimental work.

Section 58.130 Conduct of a nonclinical laboratory study.

1. Does raw data collected in nonclinical laboratory studies have to be cosigned be a second individual.

No.

2. What are the GLP requirements that are applicable to computerized data - acquisition systems?

An acceptable system must satisfy the following criteria:

(1) Only authorized individuals can make data entries,

(2) data entries may not be deleted, but changes may be made in the form of dated amendments which provide the reason for data change,

(3) the data base must be made as tamperproof as possible,

(4) the SOPs should describe the procedures used for ensuring the validity of the data, and

(5) either the magnetic media or hard-copy printouts are considered to be raw data.

3. In Japan, employees do not sign raw data records but rather they use an official seal which is unique to the employee. Is this an acceptable procedure? Yes.

4. Do tissue slides have to carry the complete sample labeling information stated in the GLPs?

No, accession numbers are permitted providing that these numbers can be translated into the information required under Section 58.130 ?

5. Is a positive notation (a statement of what was done in the raw data) required for routine laboratory operations such as:

(a) identifying animal,

(b) shaving or abrading rabbits,

(c ) specific dosing procedures, and

(d) fasting of animals? Yes.

6. Do the GLPs require the entry of raw data into bound notebooks? No.

7. Is it acceptable to manually transcribe raw data into notebooks if it is verified accurate by signature and date?

Technically the GLPs do not preclude such an approach. It is not a perferred procedure, however, since the chance of transcription errors would exist.

Accordingly, such an approach should be used only when necessary and in this event the raw data should also be retained.

SUBPART J

RECORDS AND REPORTS

Section 58.185 Reporting of nonclinical laboratory study results.

1. Do contributing scientist's reports have to be prepared and appended to final reports or can the contributing scientist's report be included in the final report prepared by the study director and signed by each contributing scientist?

The signed reports of contributing scientists should be appended to the final report.

2. Does Section 58.115(a) describe the format for submission of a final report?

The cited section describes the information that has to be submitted in a final report but the specific format is left up to the laboratory.

3. Do all circumstances that may have affected the quality of the data have to be described in the final report?

Yes.

4. Who approves the final report of a nonclinical laboratory study?

The GLPs do not address the issue of approval of the final report. According to the GLPs, the final report is official when it is signed and dated by the study director. If persons reviewing the final report request changes, then such changes must be made by way of a formal amendment.

5. Can the chemistry information required by Section 58.185(a)(4) be located elsewhere in the application for a research or marketing permit?

Yes. The final report should, however, reference the location of the chemistry information.

6. Does everyone who participated in a study have to be identified in the final report?

No. The final report need identify only the name of the study director, the names of other participating scientists, and the names of all supervisory personnel.

7. Does the phase of the study which has been inspected need to be identified in the QAU statement in the final report? No.

8. How are protocol deviations which are discovered after the completion of the study to be handled?

The deviations should be described in the final report and in the study records.

9. How does the agency view interim reports of nonclinical laboratory studies?

Interim reports are to be treated the same as final reports, i.e. they are to be reviewed by the QAU so that the summarized data accurately reflects the raw data.

Section 58.190 Storage and retrieval of records and data.

1. Certain raw data records are not study specific (pest control, instrument calibration). Must these be filed in the archives in each study file?