DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration
AGENCY: Food and Drug Administration.
21 CFR Part 58
Good Laboratory Practice Regulations
[Docket No. 83N-0142]
52 FR 33768
September 4, 1987
ACTION: Final rule.
SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule that
amends the regulations that specify good laboratory practice (GLP) for nonclinical
laboratory studies. The amendments clarify, delete, or amend several provisions of the GLP
regulations to reduce the regulatory burden on testing facilities. The changes will also
achieve a substantial reduction in the paperwork burden imposed upon the regulated
industries by the current regulations. Significant changes are made in the provisions
respecting quality assurance, protocol preparation, test and control article
characterization, and retention of specimens and samples based on FDA's experience in
implementing the regulations. The agency has determined that the changes will not
compromise the objective of the GLP regulations, which is to assure the quality and
integrity of the safety data submitted in support of the approval of regulated products.
EFFECTIVE DATE: October 5, 1987.
FOR FURTHER INFORMATION CONTACT: Paul D. Lepore, Office of Regulatory Affairs
(HFC-230), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857,
301-443-2390.
TEXT: SUPPLEMENTARY INFORMATION:
Background
In the Federal Register of October 29, 1984 (49 FR 43530), FDA published a proposal to
amend the agency's regulations in 21 CFR Part 58, which prescribe good laboratory practice
for conducting nonclinical laboratory studies (the GLP regulations). The proposal was the
result of an evaluation of the GLP regulations and of the data obtained by the agency's
inspection program to assess laboratory compliance with the regulations. The evaluation
led the agency to conclude that some of the provisions of the regulations could be revised
to permit nonclinical testing laboratories greater flexibility in conducting nonclinical
laboratory studies without compromising public protection. FDA invited comments on all
aspects of the proposal and provided 60 days for interested persons to submit comments,
views, data, and information on the need to revise any other provisions of Part 58.
Comments
FDA received 33 comments: 19 from manufacturers of articles regulated by FDA, 4 from
associations, 8 from foreign or domestic testing or consulting laboratories, and 2 from
individuals within FDA. The majority of these comments endorsed the proposed changes. Many
of the comments suggested additional revisions to the GLP regulations or modifications to
the proposed changes. A summary of the comments received by FDA during the comment period
and the agency's response to them follows.
General
1. One comment urged FDA to initiate training procedures for its field
personnel so that the regulated community would obtain maximum benefit from the revisions
to the GLP regulations.
FDA agrees that agency field personnel who conduct inspections of
nonclinical testing laboratories need to understand the specific requirements of the GLP
regulations to follow appropriate inspectional practices and procedures. FDA has, to date,
conducted 17 training courses at its National Center for Toxicological Research in
Jefferson, AR, to provide training in good laboratory practice and the associated
laboratory inspection techniques. FDA intends to continue to provide such training for its
personnel.
2. Eight comments urged FDA to encourage the Environmental Protection
Agency (EPA) to adopt similar revisions to its good laboratory practice standards. The
comments noted that unless EPA amends its good laboratory practice standards to conform
them to FDA's GLP regulations, nonclinical laboratories will still be required to comply
with EPA's more stringent requirements. Therefore, regardless of any changes that FDA
makes in its regulations, laboratories will not benefit from the revisions unless the EPA
regulations are similarly revised.
FDA recognizes that certain nonclinical laboratories that are subject to
FDA's regulations are also subject to the good laboratory practice standards established
by EPA under the Federal Insecticide, Fungicide and Rodenticide Act (7 U.S.C. 135 et seq.)
and the Toxic Substances Control Act (15 U.S.C. 2600 et seq.). When this final rule
becomes effective, some of the provisions of the GLP regulations will differ from the good
laboratory practice standards established by EPA. FDA has consulted with EPA officials
respecting the changes to FDA's regulations effected by this final rule and will cooperate
fully with EPA when that agency propose to revise its regulations.
Scope
3. Except for editorial changes to § 58.1, FDA did not propose to change
the scope of Part 58. One comment, however, urged the agency to revise § 58.1 further to
make clear that batch release safety tests performed on specific batches of biological
products intended for use in clinical trials after tests to establish the basic safety
profile have been conducted are subject to the GLP regulations.
FDA declines to change final § 58.1 on the ground that the studies
described by the comment are within the current scope of Part 58. The animal tests
performed with an investigational biological product prior to licensing, including the
batch release safety tests, are intended to establish the safety of the product.
Accordingly, any such test would constitute a nonclinical laboratory study as defined in
§ 58.3(d). Because such test would also be intended to support a marketing application
for a product regulated by FDA, it would be subject to the GLP regulations.
Definitions
4. Four comments endorsed FDA's proposal to change the definition of
"control article" in § 58.3(c) to exclude from the definition feed and water
administered to control groups of a test system. One comment, however, expressed concern
that, by relaxing essential standards, the proposed change would compromise the quality of
the animal test.
FDA does not agree that excluding feed and water from the definition of
"control article" will compromise test quality. The regulations will continue to
contain provisions adequate to control the use of feed and water in a nonclinical
laboratory study. For example, § 58.31(e) requires management to assure that materials
are available as scheduled, § 58.45 provides for proper feed storage, § 58.81(b)(2)
requires the preparation of standard operating procedures for animal care (e.g.,
nutrition), § 58.90(g) requires periodic analysis of feed and water for interfering
contaminants, and final § 58.120(a)(7) (formerly § 58.120(a)(9)) requires the protocol
to contain a description or an identification of the diet, including specifications for
acceptable levels of contaminants. Other sections of the regulations also apply to feed or
water that is used as a carrier for the test or control article. For example, § 58.31(d)
requires management to assure that test and control article mixtures have been
appropriately tested, § 58.47 requires that a testing facility include storage areas that
are adequate to preserve the identity, strength, purity, and stability of such mixtures,
and § 58.113 requires the laboratory to conduct appropriate analyses for uniformity of
the mixture, as well as concentration and stability of the test article in the mixture. As
discussed at length in the preamble to the proposal (49 FR 43531), the amendment to §
58.3(c) will mean that the feed and water provided to the control groups of a test system
will not be subject to certain provisions of the regulations, e.g., those requiring
control articles to be characterized and tested for stability (§ 58.105), retained as
reserve samples (§ 58.195), or accountable with respect to use (§ 58.107). As
discussed above, however, the regulations will continue to require the provision of
adequate supplies of feed and water, a description of the feed, proper storage, and use
accountability procedures as directed by the protocol, and standard operating procedures.
Further, only feed and water shown to be free from unacceptable contamination may be used
in a study.
For the reasons above, FDA concludes that the change to § 58.3(c) will
not compromise the quality of the animal test and that the term "control
article" should be reserved for the discrete substances/articles and vehicles other
than feed and water administered to groups of the test system to provide a basis of
comparison with the test article.
5. Four comments on proposed § 58.3(d) endorsed FDA's proposal to allow
laboratories to conduct several experiments using the same test article under a single,
comprehensive protocol. One comment, however, expressed concern that by amending the
definition of "nonclinical laboratory study," FDA may inadvertently encourage
laboratories to establish protocols that (1) are too brief to assure the quality and
integrity of safety data developed through a study conducted under the protocol, or (2) do
not describe study procedures in sufficient detail for such assurance, because lengthy
"umbrella protocols" may be difficult to administer and track during the
amendment process.
Under the revised definition in § 58.3(d), a single "umbrella"
protocol may be used for concurrent testing of more than one test article using a single
common procedure, e.g., mutagenicity testing, or for a battery of studies of one test
article conducted in several test systems. Section 58.120 requires that each study
have an approved written protocol that clearly indicates the objectives and all methods
for the conduct of the study, and § 58.33 requires the study director to assure that the
protocol is approved and followed.
FDA notes that the changed definition of "nonclinical laboratory
study" does not require any laboratory to establish "umbrella" protocols --
it only allows it as an option. The agency recognizes that a longer, more complex protocol
might be more difficult to manage than a simpler one; however, using an
"umbrella" protocol should be more efficient than using several closely related
protocols. The quality or accuracy of test data and procedures should not be compromised,
while the paperwork burden should be reduced. In any event, the laboratory remains
responsible for assuring that the validity of any study that it conducts is not adversely
affected due to an inadequate protocol.
6. One comment urged FDA to revise further the definition of nonclinical
laboratory study to define the terms "study initiation" and "study
termination."
FDA recognizes that differing words and phrases are used within the GLP
regulations to denote dates respecting significant events that occur during a laboratory
study. For this reason, the agency agrees that it may be useful to add to the
regulations definitions of the terms "study initiation" and "study
completion."
FDA advises that the study initiation date represents the date on which
the study director has completed plans in preparation for the technical conduct of a study
(see § 58.33) and on which, under § 58.31(e), management is required to make certain
that personnel, resources, facilities, equipment, materials, and methodologies for the
study are available as scheduled. On the study initiation date, the study is entered on
the master schedule sheet (see § 58.35(b)(1)). After this date, any protocol changes are
to be made only in accordance with the procedure described in § 58.120(b). Accordingly,
FDA is adding new § 58.3(o) to define "study initiation" to mean the date the
protocol is signed by the study director.
The study completion date is the date on which the study director signs
the final report (see final § 58.185(b)). On the study completion date, the study
director is required to make certain that raw data, documentation, protocols, specimens,
and final reports are transferred to the archives (see § 58.33(f)), and under § 58.35,
the quality assurance unit may retire the study from the master schedule sheet. This
date also specifies the beginning of the record retention period under § 58.195(b). After
the study completion date, final reports may be amended only in accordance with the
procedure described in § 58.185(c). Accordingly, FDA is adding new § 58.3(p) to
define "study completion" to mean the date the final report is signed by the
study director. As a necessary conforming amendment, FDA is also amending § 58.185(b) to
provide that the final report shall contain the dated signature of the study director.
FDA advises that the phrase "close of the study" as used in §
58.33(f) refers to the study completion date. Also, the terms "terminate" and
"discontinue" as used in § 58.195(b)(3) are used in their ordinary senses to
mean stop, cease, break off, or give up, denoting that a study has been ended before the
planned study completion date. For these reasons, FDA believes that these terms do
not need any further definition to make clear their meanings.
7a. Three comments urged FDA to expand the definition of "raw
data" under § 58.3(k) to provide that the computer record of "hand-recorded
data entered into the computer verbatim and verified" could be substituted for the
original source as raw data.
FDA does not agree that the computer record of hand-recorded data may be
considered as raw data. Individuals who enter data from a laboratory study into the
computer commonly do not have any knowledge of the conditions under which the data were
collected and may not understand the data originator's notations that regularly are
included on the hand-recorded data sheets. The probability of error in data entry is
greatly increased under these circumstances.
7b. One comment urged the agency to revise § 58.3(k) to make clear that
the term "raw data" as it pertains to the findings of the histopathological
examinations refers only to the signed and dated final report of the pathologist.
FDA does not agree that it needs to amend the definition of raw data
relative to the findings of histopathological examinations. In pertinent part, § 58.3(k)
defines raw data as laboratory worksheets, records, memoranda, notes, or exact copies
thereof, that are the result of original observations and activities and are necessary for
the reconstruction and evaluation of the final report. Although the notes taken by a
pathologist during histopathological examination of slides are indeed the result of
original observations, these notes are not necessary for the reconstruction and evaluation
of the final report. The final report is evaluated by an analysis of the pathology
syndrome as described in the pathologist's report, which is required under §
58.185(a)(12). Further, because § 58.190(a) requires histopathological blocks, tissues,
and slides to be retained as specimens, the final report can be reconstructed by
verification of the pathology findings by, e.g., a second pathologist or by a team of
pathologists.
The pathologist's interim notes, therefore, which are subject to frequent
changes as the pathologist refines the diagnosis, are not raw data because they do not
contribute to study reconstruction. Accordingly, only the signed and dated final report of
the pathologist comprises raw data respecting the histopathological evaluation of tissue
specimens.
Testing Facility Management
8. One comment objected to FDA's proposal to delete the provision in §
58.31(b) that requires testing facility management to document as "raw data" the
replacement of a study director. The comment argued that it could be difficult to retrieve
such documentation if data were transferred to another location after completion of a
study.
FDA proposed to delete the requirement in § 58.31(b) to document study
director replacement as "raw data" in the agency's belief that other provisions
of the GLP regulations adequately require documentation of this event. The agency
continues to believe that the requirement in § 58.31(b) is redundant to such other
provisions and is not necessary to assure the quality and integrity of the safety data
developed through a study conducted by a laboratory. For example, § 58.35(b)(1) provides
that the master schedule sheet shall contain the name of the study director. Thus,
replacement of the study director would necessitate an updating of the master schedule
sheet. The master schedule sheet itself is "raw data" because it is a record
that is the result of laboratory activities and is necessary for the reconstruction of the
study. Also, § 58.120(b) requires that any change in an approved protocol and the reason
or reasons for the change are to be documented. Because § 58.120(a)(11) of the final rule
(previously § 58.120(a)(15)) requires that the protocol contain the dated signature of
the study director, replacement of the study director would constitute such a change.
Other provisions of the regulations require the quality assurance unit to retain the
master schedule sheet and copies of protocols as an easily accessible system of records
for a specified period after completion of the study (§ 58.195(d)). Therefore, it should
not be difficult to identify the term of each study director even if records are
transferred elsewhere after study completion.
Study Director
9. Several comments objected to § 58.33 in its entirety on the grounds
that (1) the regulation does not clearly define the responsibility of the study director
and (2) the wording of the regulation implies that the study director must be technically
competent in all areas of a study. One comment argued that the study director should be
responsible only for "coordinating" the technical conduct, interpretation,
analysis, documentation, and reporting of results.
FDA discussed at length in the preamble to the GLP final rule the intent
of § 58.33 and the requirements applicable to the individual who is designated the study
director for any study (43 FR 59986, 59995; December 22, 1978). As discussed in that
preamble, the study director represents the single, fixed point of responsibility for
overall conduct of each study. Although "coordination" of the pieces of a study
logically is part of the study director's responsibilities, to limit his or her
responsibilities to mere "coordination" would compromise public protection if
another person were not such designated fixed point and would add an unnecessary burden if
FDA were to require a laboratory to employ an additional person to provide such a point.
The study director is charged with the technical conduct of a study, including
interpretation, analysis, documentation, and reporting of results. FDA does not intend,
however, that the individual is to be technically competent in all areas of a study. FDA's
inspectional experiences have demonstrated that if responsibility for proper study conduct
is not assigned to one person, a potential exists for the issuance of conflicting
instructions and improper protocol implementation.
FDA concludes that the comments did not provide any new data or
information to negate the agency's original determinations and that it should retain §
58.33 as it was established in the December 22, 1978, final rule.
10. One comment objected to FDA's proposal to delete the phrase "and
verified" from § 58.33(b), which currently requires that the study director assure
that all experimental data are "verified" as well as accurately recorded. The
comment argued that removing the study director's obligation to assure that the data have
been verified would dilute the responsibility of the study director for proper conduct of
the study.
FDA has carefully reevaluated its proposal to remove the phrase "and
verified" from § 58.33(b). FDA proposed to delete the phrase from the regulation in
response to arguments from management of testing facilities that they misinterpreted the
provision, apparently believing that it required the study director personally to witness
each data observation. FDA did not intend the provision to so require. Rather, the agency
regards the study director as responsible for assuring that all experimental data are
verified.
Ordinarily the verification required by § 58.33(b) is obtained by the
individual collecting the data, using data verification procedures described in the
protocol or in the specific standard operating procedure, and by the individual's
supervisor as part of the supervisory quality control procedures. "Verified" is
used to describe the study director's responsibility to assure the accurate recording of
data. Verification in this sense does not require the study director to observe every data
collection event but does require the study director to make certain that the study
conduct procedures designated in the protocol for a study and the standard operating
procedures established for a study are followed. For all these reasons, FDA has decided to
retain the phrase "and verified" to confirm the need for data verification in
nonclinical laboratory studies.
11. Two comments urged that the study director's responsibility for
assuring placement in the archives of the study records specified under § 58.33(f) be
transferred to testing facility management under § 58.31. The comments argued that raw
data and documentation are under the immediate control of facility management rather than
the study director.
The change suggested by the comments would conflict with the study
director's responsibility identified in § 58.33 of representing the single point of study
control (see paragraph 9 of this preamble). The archived materials of each study,
including raw data and documentation, constitute lasting proof of study validity. The
transfer of such materials to the archives is a critical step in study control that
assures that the archived materials are complete and adequate for study reconstruction.
Indeed, these revised regulations further emphasize the study director's control function
by defining the study completion date as the date the final report is signed and dated by
the study director; after this date, the study director assures that all required
materials are transferred to the archives. Consequently, FDA declines to accept the
change proposed by the comments.
Quality Assurance Unit
12. FDA received eight comments regarding § 58.35(a), which sets forth
the composition and function of the Quality Assurance Unit (QAU). One comment endorsed
FDA's proposal to substitute "which" for the current phrase, "composed of
one or more individuals who," to make clear the personnel who can perform quality
assurance duties. The comment suggested, however, that the agency use the term
"function" or "activity" in § 58.35(a) in place of the current term
"unit" to make it clear that quality assurance monitoring need not be performed
by individuals of a permanently staffed unit. Four comments disagreed strongly with the
proposed change to § 58.35(a), arguing that the change inappropriately implies that
assurance of a well-conducted study does not require special training or experience. The
comments also asserted that verifiable data are produced as a result of the current
requirement for an independent, fixed and permanently staffed quality assurance unit.
Other comments argued that individuals should not monitor studies similar to their own
work. Some comments requested further clarification of the required composition of the
QAU.
FDA does not believe that identification of the quality assurance unit as
a "function" or "activity" would serve to clarify the composition or
function of the QAU. FDA never has intended that the QAU necessarily has to be a separate
entity or a permanently staffed "unit" (see 43 FR 59996). "Quality
assurance unit" has become an accepted term to describe those individuals responsible
for quality assurance as described in § 58.35. FDA also does not agree that the proposed
revision to § 58.35(a) implies that assurance of a well-conducted study does not require
special training or experience on the part of individuals monitoring the conduct and
reporting of a nonclinical laboratory study. FDA continues to believe that well-qualified
and trained personnel are essential to quality assurance under the GLP regulations and
that one of management's most important responsibilities in maintaining effective quality
assurance is to provide an adequate number of such personnel (§ 58.31 (c) and (e)).
FDA concludes from the comments that the requirements set forth in §
58.35(a) have been misinterpreted in some instances to mean that the regulations require
that the QAU be composed of individuals whose sole duties are in quality assurance. In
fact, the agency intends only that quality assurance activities be separated from study
direction and conduct activities; that is, a trained and qualified person who works on one
study can perform quality assurance duties on any study in which he or she is not
involved. FDA's reason for requiring separation of quality assurance functions from study
conduct functions is fundamental -- to assure that quality assurance personnel can act
candidly, without bias or a real or perceived conflict of interest. In effecting the
separation required by the GLP regulations, FDA was aware that many small laboratories
could not afford the operation of a permanently staffed QAU. For this reason, the agency
concluded that the separation of functions on a study-by-study basis as permitted in the
existing and revised regulations would provide effective quality assurance. The agency's
intent in defining the composition and function of the QAU was discussed at length in the
preamble to the current GLP regulations (see 43 FR 59996). FDA believes that the change
now being made more clearly reflects the agency's original intent.
13. One comment recommended that FDA delete the word "sheet"
from the term "master schedule sheet" in § 58.35(b)(1) on the ground that there
are methods for maintaining a master schedule other than use of an actual
"sheet."
FDA acknowledges that current technology allows for various methods for
maintaining a master schedule, ranging from sophisticated computerized procedures to
procedures whereby such information is contained in written records. Regardless of
the method utilized, however, the master schedule information is "raw data"
within the meaning of the GLP regulations and copies of the master schedule are required
to be retained in the study archives in accordance with § 58.195(b). The agency is,
therefore, retaining the term "master schedule sheet" to emphasize that the
master schedule constitutes raw data subject to agency inspection and that the records
must be retained.
14. One comment suggested that FDA delete the current provision in §
58.35(b)(1), which requires a laboratory to include the name of the sponsor of each study
on the master schedule sheet for all studies conducted at the facility. The comment
urged the agency to allow sponsor identification by code.
FDA agrees that including the sponsors' name on the master schedule sheet
is not essential either for the conduct of management's functions listed in § 58.31 or
for the conduct of proper quality assurance under § 58.35. Sponsor identification
by code is an adequate procedure, provided that the name of any sponsor is made available
to FDA upon request. Accordingly, FDA is amending § 58.35(b)(1) to read "* * *
identity of the sponsor * * *."
15. One comment suggested that FDA further revise § 58.35(b)(1) to allow
the master schedule sheet to be indexed by study number rather than test article on the
ground that multiple studies may be performed on each test article.
FDA recognizes that a nonclinical laboratory may have in progress several
studies on each test article that is listed on the master schedule sheet. The agency
concludes, however, that indexing by study number alone and not by test article would be
inappropriate. The master schedule sheet is the mechanism through which the QAU can assure
management that the facilities are adequate and that there are sufficient numbers of
qualified personnel available to accomplish the scheduled work (see 43 FR 59997). In
addition, § 58.31(e) requires management to assure that study materials (e.g., test
articles) are available as scheduled. The use of study numbers rather than test articles
as index terms would, therefore, frustrate a major purpose of the master schedule sheet
and impede the conduct of an important management function.
16. Three comments endorsed FDA's proposal to delete the current
requirement under § 58.35(b)(1) that the status of the final report be a distinct entry
on the master schedule sheet. One comment, however, objected to the proposal on the basis
that frequently there are delays in completing the final report, and the study status
often is different from the expected date of completion of the report.
FDA believes that the comment that objected to the proposal misconstrued
the purpose of revising § 58.35(b)(1). Section 58.35(b)(1) currently requires that
the master schedule sheet contain separate headings for the "current status" of
the study and for the "status of the final report" of the study. FDA considers
the preparation of the final report to be a study event, current status of which should be
reflected on the master schedule sheet. Preparation of the final report is similar
to other study events (e.g., test article-mixture preparation, test system dosing, in life
observations) that are listed under "current status." Under this revision to §
58.35(b)(1), the master schedule sheet would contain the same information respecting the
final report as is required under the current GLP regulations, but the information would
be included only under the "current status" heading. The agency advises that
"expected date of completion of a final report" is not a "status"
entry. Such information has not been required in the past nor is this information being
required now.
17. FDA proposed to revise § 58.35(b)(3) to provide specifically that the
QAU need only inspect "each nonclinical laboratory study" on a schedule adequate
to assure the integrity of the study. Four comments recommended that the agency further
revise the regulation to substitute the word "studies" for the phrase "each
nonclinical laboratory study" alleging that inspection of multiple short duration
studies can result in expenditure of significant time and effort with little derived
benefit. Two comments argued that inspection of short duration studies conducted
repeatedly at the same facility by the same personnel is not necessary and suggested that,
in lieu of requiring inspection of each study, standard operating procedures be developed
to determine the inspection frequency of various types of studies. These comments also
recommended that such inspections be used to demonstrate compliance of other similar
studies conducted in the same time frame.
FDA does not agree with the comments. The quality of each nonclinical
laboratory study submitted to the agency in support of an application for a research or
marketing permit for a product regulated by FDA is critical to a determination of the
safety of the product. The principle of quality assurance advanced in the GLP regulations
is to inspect studies to identify and correct problems in a timely fashion. FDA is
convinced that such problems can be detected only through a program of vigorous inspection
of each study. This does not mean, however, that every phase of every study needs to be
inspected by the QAU (see paragraph 18 of this preamble).
18. Two comments disagreed with FDA's proposal to modify the current
requirement in § 58.35(b)(3) that the QAU inspect each phase of a study at specified
intervals. The comments argued that elimination of specified quality assurance inspection
intervals may result in decreased compliance by cost-cutting laboratories. Another comment
urged FDA to identify the critical phases of a nonclinical laboratory study to be
inspected by the QAU.
Section 58.35(b)(3) currently provides that the QAU is to inspect at
periodic intervals each phase of a nonclinical laboratory study. For studies lasting more
than 6 months, the inspections are to be conducted every 3 months. For studies lasting
less than 6 months, the inspections are to be conducted at intervals adequate to assure
the integrity of the study (including each phase at least once). The term "each
phase" was intended to emphasize the need for repeated surveillance so that the QAU
observes at least once during the course of the study each critical operation. The term
"periodic" was included in the regulation to indicate the need for more than one
inspection of certain repetitive, continuing operations. In light of current information,
however, FDA does not believe that such a rigid schedule is essential to assure study
quality. The agency has learned through its inspection program that the quality of
toxicology testing is much higher than that envisioned in 1976 when FDA proposed to
establish the GLP regulations (see 41 FR 51206, 51207-51208; November 19, 1976).
Contemporary concepts of quality assurance emphasize the effectiveness of
thorough, in-depth inspections of study processes (i.e., all operations required to
accomplish a study phase) in place of quick, spot checks of individual operations with a
study. Thorough examination of personnel, facilities, equipment, standard operating
procedures, data collection procedures, raw data books, and other features associated with
a study phase can achieve more effective quality assurance than does a more superficial
observation of the conduct of the same study phase in a series of studies.
The agency has concluded that the QAU's inspection schedule should take
into account the need for inspection of each study on a schedule adequate to assure the
integrity of the study being monitored. The change in § 58.35(b)(3) permits the QAU to
exercise reasonable flexibility and judgment so that inspections can be scheduled to best
achieve the goal of assuring that studies are properly conducted. The agency advises,
however, that each study, no matter how short, needs to be inspected in-process at least
once. Further, across a series of studies all phases should be inspected in order to
assure the integrity of the studies. For these reasons, FDA does not believe that the
regulation as revised will result in decreased compliance with the GLP regulations or that
the term "critical phase" needs to be defined.
19. Eight comments addressed FDA's proposal to delete § 58.35(b)(4),
which currently requires the QAU to submit periodic written status reports to management
and to the study director. One of the comments supported the proposal on the basis that
the provisions of § 58.35(b)(3), which require reports to management on problems likely
to affect study integrity, are adequate to assure study quality. Several comments
questioned whether deleting § 58.35(b)(4) would provide any practical benefit to testing
facilities, noting that management is likely to continue to expect periodic reports. One
comment noted that elimination of the requirement for status reports could allow
management to disregard quality assurance problems if management is only marginally
supportive of good laboratory practice and quality assurance. Three comments argued that,
by deleting the provision, FDA would inappropriately place on the QAU rather than on the
study director the obligation of determining what constitutes a problem likely to affect
the integrity of a study. One comment argued that, because management is required to be
involved in corrective actions under the provisions of §§ 58.31(g) and 58.35(b)(3),
management must be kept informed respecting the status and the progress of any study
inspected by the QAU. Another comment suggested that FDA delete the requirement that
status reports be provided to the study director but retain the requirement that
management receive such reports.
After careful consideration of these comments, FDA has concluded that §
58.35(b)(4) should be retained in its current form. The agency proposed to delete the
paragraph based on its tentative conclusion that routine reports of unremarkable findings
by the QAU are not essential to study quality. The comments, however, are persuasive in
that such reports are necessary to demonstrate to management that the QAU is functioning
properly. It is also necessary that the study director continue to receive such reports
because that individual is responsible for all aspects of any study being conducted by a
facility, including GLP compliance.
20. One comment suggested that, in lieu of deleting the entire paragraph,
§ 58.35(b)(4) be modified by removing the requirement for status reports on each study,
thereby reducing paperwork.
In accord with the conclusions stated in paragraph 19 of this preamble,
FDA believes that it is inappropriate to eliminate the requirement for status reports for
each study. Without status reports on each study, there would not be adequate
assurances concerning the quality of the ongoing studies.
21. One comment urged FDA to revise current § 58.35(b)(5) to hold the QAU
responsible only to (1) determine that known deviations from approved protocols or
standard operating procedures were not made without proper documentation, and (2) require
authorization for anticipated deviations. The comment argued that the current wording of
the regulation implies that the QAU shall have prior knowledge of any deviations and shall
approve such deviations, which is not the case in most instances.
FDA would not consider a laboratory to have violated § 58.35(b)(5) if a
deviation was not authorized in advance because it was unanticipated. For example, as
recognized in the preamble to the final rule (43 FR 59998), a fire in the facility would
necessitate immediate action. Also, as discussed at length at 43 FR 59998, FDA does not
intend that the QAU is responsible for authorizing any deviations from the protocol or
standard operating procedures, rather it is responsible for detecting any such deviations
by its inspection and audit procedures. The revision suggested by the comment would remove
the accountability of the QAU for detecting deviations and would undermine the
requirements for quality assurance.
22. FDA proposed to revise current § 58.35(b)(7) to provide that the
statement which the QAU prepares to accompany the final report would be required to
identify the phases of the study inspected and the number of inspections conducted. Eleven
comments objected to the proposed change to the regulation, which currently requires only
that the statement by the QAU specify the dates that inspections of the study were made
and the dates that findings were reported to management and to the study director. Most of
the comments were concerned with the additional reporting burden imposed by the proposed
revision. Some of the comments argued that the information sought by FDA through the
proposed revision in § 58.35(b)(7) is currently required under the provisions of § 58.35
(b)(3) and (c). These comments pointed out that requiring additional documentation would
be duplicative and contrary to the stated purposes of the proposed revisions to the GLP
regulations.
FDA has carefully reevaluated its proposal to require that the QAU
statement identify the phases of a study inspected and the number of inspections
conducted. The agency is persuaded that the proposal would have provided information
redundant to that which is available under other provisions of the GLP regulations.
Accordingly, FDA has decided not to change § 58.35(b)(7) and is retaining this provision
in its current form. Proposed § 58.35(b)(6) (as § 58.35(b)(7) would have been
renumbered) is not being adopted.
Animal Care Facilities
23. One comment objected to the proposed modification to § 58.43(c),
which would delete the current requirement that all laboratory facilities include separate
areas for the diagnosis, treatment, and control of laboratory animal diseases. The comment
noted that animal health is a major problem in toxicology testing. For this reason, the
comment argued that any relaxation of the current requirements in the GLP regulations for
animal care is ill-advised and contradictory to FDA's responsibility for the welfare of
animals.
As discussed in the preamble to the proposed amendments to the GLP
regulations (49 FR 43532), a laboratory may elect to dispose of diseased animals, thereby
obviating the need for dedicated areas for such animals. FDA believes that it is not
cost-effective to require separate areas in every case and has concluded that the decision
concerning appropriate separation of animals should be made by the study director in
consultation with other scientific personnel. The agency does not believe that providing
for dedicated laboratory areas as appropriate compromises FDA's continuing commitment to
animal welfare, which is specifically dealt with in § 58.90. Indeed, FDA believes that
the GLP regulations foster quality animal testing under defined conditions so that fewer
animals are required to establish product safety.
Animal Supply Facilities
24. FDA proposed to revise § 58.45 to permit laboratories to store
perishable supplies or feed by methods most appropriate to the characteristics of the
materials. One comment urged FDA to amend § 58.45 further to permit storage of
animal feed in rooms housing small animals or small groups of animals that are isolated
from other studies.
FDA declines to amend § 58.45 as recommended by the comment. In
developing the current GLP regulations, the agency carefully considered whether animal
feed or bedding might be stored within any test areas. FDA concluded at that time that
storage areas needed for feed and bedding should be separate from the areas housing the
test system to preclude mixups and contamination of test article-carrier mixtures and
inadvertent exposure of the test system to potentially interfering contaminants. FDA
continues to believe that separate storage areas for feed and animal bedding should be
required and the comment did not provide any data to counter this belief. FDA advises,
however, that § 58.45 does not preclude holding of limited quantities of test or control
article-feed mixtures for short periods of time in properly constructed and labeled
containers in the animal rooms.
25. One comment objected to the proposed changes to § 58.47, arguing that
it believed the current requirements respecting facilities for handling test and control
articles have resulted in fewer mixups.
Based on the comment, FDA has reconsidered the proposed revision of §
58.47. The agency agrees with the comment, in principle. Indeed, the agency intended the
revision to be only editorial to simplify and to make clear that laboratories shall
provide separate areas for receipt, mixing, and storage of test and control articles and
their mixtures as necessary to prevent contamination or mixups. Inadvertently,
however, the proposed revision would have deleted an essential requirement of good
laboratory practice, i.e., the need to provide storage areas for test and control article
mixtures adequate to preserve the identity, strength, purity, and stability of the
mixtures. For this reason, the agency has concluded that the regulation is
appropriate as currently stated and existing § 58.47 is retained.
Maintenance and Calibration of Equipment
26. FDA proposed to revise § 58.63(b) to provide that written standard
operating procedures respecting maintenance and calibration of equipment would allow
laboratories to discard faulty equipment as an alternative to the current provisions of §
58.63(b), which provide only for the repair of equipment that fails or malfunctions. Under
FDA's proposal, a testing facility would need to specify remedial action in the event of
equipment failure or malfunction only when remedial action is "appropriate" to
the particular piece of equipment. Three comments recommended that FDA amend § 58.63(a)
to require testing, calibration, and/or standardization of equipment in accord with
written standard operating procedures. The comments argued that by changing current §
58.63(a) in this fashion, FDA might delete § 58.63(b) in its entirety without
substantively affecting the requirements of the GLP regulations applicable to laboratory
equipment.
FDA advises that § 58.63(b) concerns not only setting forth in standard
operating procedures the details of routine inspection, cleaning, maintenance, testing,
calibration, and/or standardization of equipment, but it also concerns describing remedial
actions to be taken when appropriate if the equipment fails or malfunctions. In
promulgating existing § 58.63(b), FDA concluded that the specific features set forth in
the regulations need to be included in equipment standard operating procedures because of
the crucial role that properly used equipment plays in study conduct; a role which
pervades every phase of a study and is vital to study quality and final report integrity.
The comments did not provide any data that negate FDA's original determination. The
agency continues to believe that specification of these features provides useful guidance
to persons subject to the GLP regulations and concludes, therefore, that it would be
inappropriate to delete § 58.63(b) from the regulations.
27. Section 58.63(b) requires in part that written standard operating
procedures designate the person responsible for certain operations respecting equipment,
i.e., routine inspection, cleaning, maintenance, testing, calibration, and/or
standardization. Although FDA did not propose to revise these requirements of § 58.63(b),
three comments stated that by requiring that standard operating procedures designate an
individual responsible for performing each operation, FDA obligates testing facilities to
change their standard operating procedures frequently. The comments further argued
that the requirement to make a copy of the standard operating procedures available to
laboratory personnel is redundant to the requirements set forth in § 58.81(c) and should
be deleted.
The comments misconstrue the meaning of the word "person" as it
is used in § 58.63(b). The second sentence of § 58.63(b) requires, in pertinent part,
that "the written standard operating procedures shall designate the person
responsible for the performance of each operation * * *." As explained in paragraph
120 of the preamble to the final rule (43 FR 60001), FDA adopted the term
"person" as defined in § 58.3(h) rather than the originally proposed term
"individual" to allow the standard operating procedures to designate an
organizational unit.
The agency agrees with the comment that § 58.63(b) is redundant to §
58.81(c) insofar as it provides for standard operating procedure availability.
Accordingly, FDA is removing the phrase "and copies of the standard operating
procedures shall be made available to laboratory personnel" from § 58.63(b).
28. Section 58.63(c) requires that a testing facility maintain written
records of all equipment inspection, maintenance, testing, calibration, and/or
standardizing operations. Two comments recommended that FDA delete § 58.63(c) in its
entirety, arguing that if management is satisfied that the standard operating procedures
are adequate, further requirements are unnecessary.
FDA does not agree with the comments. FDA carefully considered the
necessity for maintaining the records specified in § 58.63(b) when the agency developed
the current GLP regulations. FDA concluded that such records are necessary to reconstruct
a study and to ensure the validity and integrity of the data that are obtained from a
study (see paragraph 26 of this preamble and 43 FR 60001). The purpose of the record
retention requirement is to provide documentation throughout the study of equipment
function in accord with design specifications for the equipment, and equipment use in
accord with standard operating procedures for maintenance and calibration of the
equipment. FDA'S experience in administering the GLP regulations has shown the benefit of
maintaining such records. For example, through FDA's laboratory inspection program, the
agency has been able to identify the precise period of time of equipment malfunction by an
examination of the equipment records. Thus, § 58.63(c) has made it possible to disregard
the data collected by a single defective piece of equipment without having to disregard
all the data obtained from a specific study.
Standard Operating Procedures
29. Two comments on the requirements for standard operating procedures
suggested that § 58.81(a) be amended to permit appropriate supervisory personnel to
authorize deviations from the written standard operating procedures, arguing that the
study director may not have the technical expertise to evaluate such deviations. One of
the comments further argued for the change on the ground that the principles of good
laboratory practice established by the Organization for Economic Cooperation and
Development of the World Health Organization do not require study director approval of all
standard operating procedure deviations.
FDA does not accept the suggestion. As discussed in paragraph 9 of this
preamble, it is not necessary for the study director to be technically competent in all
aspects of a study to assure that appropriate action is taken in response to any
circumstances that may affect the quality and integrity of a study. The study director,
however, has to be aware of and authorize any deviations that could have an impact on the
study. FDA does not agree that the responsibility of the study director, as set forth in
§ 58.81(a), is inconsistent with the Organization for Economic Cooperation and
Development principles of GLP. Chapter 2, section 2.3 (Ref. 1, p. 27) of the Organization
for Economic Cooperation and Development document defines the responsibilities of the
study director, in part, as "ensur[ing] that the procedures specified in the study
plan are followed, and that authorization for any modification is obtained and documented
together with the reasons for them * * *." Accordingly, both the GLP regulations and
the Organization for Economic Cooperation and Development principles of GLP require that
the study director make certain that specified procedures are followed and that all
modifications to the procedures in the approved study plan (i.e., standard operating
procedures) are documented and approved.
30. One comment recommended that FDA amend § 58.81(b) to delete all
examples of standard operating procedures that FDA requires a testing facility to
establish on the ground that the list is not all-inclusive and may lead to
misinterpretation.
FDA disagrees with the recommendation. The examples listed in § 58.81(b)
are those minimal laboratory procedures which the agency believes are essential to
assuring the quality and integrity of the data generated in the course of any study (see
41 FR 51213). FDA recognizes that circumstances may necessitate establishment of
additional standard operating procedures. The list is not intended to be all-inclusive and
should not be interpreted as such.
31. Three comments objected to the proposed deletion of examples of
laboratory manuals and standard operating procedures required to be in the laboratory
under § 58.81(c). The comments argued that the listing of examples serves to spell out
the agency's intent, helps laboratories decide which areas to cover, and that without such
guidance a potential exists for misinterpretation of FDA's intent.
FDA does not agree. Section 58.81(c) requires that each laboratory area
have immediately available standard operating procedures relative to the laboratory
procedures being performed. Unlike the list in § 58.81(b), which represents specific
minimal requirements, the examples listed in § 58.81(c) encompass very broad areas. Each
of the areas presented would require the preparation of a group of standard operating
procedures to cover adequately the operations within that area. Consequently, the agency
concludes that the list in § 58.81(c) is too broad to serve as useful guidance.
Reagents and Solutions
32. FDA received five comments that recommended that the agency amend §
58.83. Four comments stated that only those reagents and solutions used in the conduct of
nonclinical laboratory studies need to be labeled in accord with the requirements of §
58.83, i.e., "to indicate identity, titer or concentration, storage requirements, and
expiration date" of the material. These comments argued that such a modification
would allow the laboratory flexibility in designing the most suitable system to assure
that deteriorated or outdated reagents and solutions are not used. The fifth comment
recommended that FDA insert into the first sentence of § 58.83 the phrase "as
appropriate" to make the provision read "all reagents and solutions in the
laboratory areas shall be labeled to indicate identity, titer or concentration, storage
requirements, and, as appropriate, expiration date." This comment argued that it was
not necessary to have expiration dates on certain stable reagents and solutions such as
water and saline.
FDA declines to amend § 58.83. The agency continues to believe, as
discussed in paragraph 148 of the preamble to the final rule (43 FR 60003), that all
reagents and solutions maintained in the laboratory area for use in the conduct of
nonclinical laboratory studies should be labeled as required by § 58.83. Accordingly, the
label should include the identity, titer or concentration, storage requirements, and
expiration date. This label information is the minimum information necessary to make clear
to the laboratory personnel that the reagents and solutions are suitable for use in the
procedures specified in the protocol and to protect against inadvertent mixups of reagents
and solutions that are used in nonclinical laboratory studies with those that are not
intended for such use. Further, FDA disagrees with the comment that suggested that
expiration dating is not necessary for some reagents and solutions. FDA believes
that expiration dates should be required on all reagents and solutions, without regard to
their stability so that there is no doubt about the suitability of the materials for use
in nonclinical laboratory studies.
Animal Care
33. One comment recommended that FDA delete § 58.90(a) on the basis that
requiring standard operating procedures for housing, feeding, handling, and care of
animals is redundant to other provisions of the GLP regulations.
FDA recognizes that § 58.81(b)(2) requires testing facilities to
establish standard operating procedures for animal care. Section 58.90(a), however,
expressly specifies that standard operating procedures shall also cover animal housing,
feeding, and handling. The agency believes that these items are essential features for
providing adequate humane treatment of animals and, therefore, is retaining § 58.90(a).
34. Two comments objected to the proposed amendment of the requirements
under §§ 58.90 (b) and (c) to provide that animals may be isolated rather than
quarantined. The comments argued that allowing laboratories to develop isolation and
health status evaluation procedures in lieu of quarantine may not provide adequate
assurance of test animal health because such evaluations are done only on a small randomly
selected number of animals and are not as reliable as an adequate quarantine period. One
comment suggested that the term "segregated" or the term "separated"
may more accurately reflect FDA's intent in amending §§ 58.90 (b) and (c) than does the
term "isolated."
As discussed in the preamble to the proposed amendments (49 FR 43533),
substitution of a requirement for isolation and health status evaluations in lieu of
quarantine of newly received animals will permit laboratories to develop specific
isolation and health status evaluation procedures in concert with the age, species, and
class of animals, and with the type of study to be done. As used in current § 58.90(b),
the term "quarantine" connotes a rigid set of prestudy procedures which a
facility is obligated to follow, including a mandatory holding period, specified
diagnostic procedures, and the use of specialized facilities and animal care practices.
The agency has concluded that isolation and health status evaluations should provide
adequate precautions against entry of unhealthy animals into a study. Health status
evaluations may be performed during the prestudy acclimation period. Under § 58.90(b),
the health status of each animal is to be evaluated soon after receipt. Section
58.90(c) prohibits the entry of any diseased animal into the study.
The agency has also concluded that a devoted area equipped to provide
isolation of diseased animals is not necessary in all cases. As discussed in the preamble
to the proposal (49 FR 43533), FDA believes that it should allow certain options for
handling diseased animals, thereby permitting increased flexibility in laboratory
operation. FDA agrees that the term "segregate" or the term
"separate" rather than the term "isolate" could be used in as much as
each term connotes "to set apart." Because "isolate" is a term
commonly used and understood in contemporary veterinary medical practice, however, FDA
will continue to use that term in these regulations.
35. One comment recommended that FDA amend § 58.90(d) to permit
procedural means to provide "appropriate identification" of individual animals
in a study.
FDA does not accept the recommendation. The agency notes that proper
animal identification throughout a study is essential to study integrity. When animals are
housed individually in cages, procedural means can be used to identify each individual
animal, i.e., a cage card may be used if it provides all the information necessary to
identify the animal specifically, and the animal handling standard operating procedures
specify detailed procedures for preventing animal mixups. The agency is not aware,
however, of any procedural means that could be used to identify adequately individual
animals that are housed within a group in a cage. FDA advises that § 58.90(d) does not
preclude identification by means other than the examples enumerated in that section
provided that individual identification can be maintained and documented throughout a
study.
Test and Control Article Characterization
36. One comment urged the agency to delete the requirement in § 58.105(b)
for stability determination of test and control articles before initiation of the study.
The comment argued that changing § 58.105(b) as recommended would make it consistent with
FDA's proposed changes to § 58.105(a), which would allow test and control article
characterization after completion of the study.
FDA disagrees with the recommendation. As discussed in the preamble to the
proposal (49 FR 43533), FDA has concluded that characterization of test and control
articles need not be performed until initial toxicology studies with the test article show
reasonable promise of the article's reaching the marketplace. In arriving at this
conclusion, the agency considered that prior knowledge of the precise molecular structure
of a test article is not vital to the conduct of a valid toxicology test. It is important,
however, to know the strength, purity, and stability of a test or control article that is
used in a nonclinical laboratory study.
A stability determination of a test or control article conducted after
completion of the nonclinical laboratory test with the article does not provide any
information about the continued strength of either the test or control article previously
given to the test system. Determining that the test and control articles are stable for
the duration of the study is fundamental to interpreting the results of the study. For
this reason, it would be inappropriate to allow for stability determinations only
after-the-fact.
The agency does believe, however, that the continued strength of the test
or control article may adequately be determined either by stability testing before
initiation of the study or through appropriate periodic analysis of each batch. Section
58.105(b) currently allows stability testing of the test and control articles through
periodic analysis only if it is not possible to determine their stability before study
initiation. Because experience has shown that it is adequate either to determine stability
of the test and control articles before initiation of a study or by periodic analysis of
the articles while the study is in progress, the agency on its own initiative is revising
§ 58.105(b) to provide facilities and sponsors the flexibility to use either approach.
Therefore, § 58.105(b) has been revised to provide for determination of the stability of
the test or control article either before study initiation or through periodic analysis of
each batch according to established standard operating procedures.
37. One comment observed that § 58.105(a) provides that testing
facilities may rely on the labeling of marketed products for purposes of characterizing
such products used as control articles in a study. The comment recommended that the agency
also revise § 58.105(b) to allow product labeling to serve as documentation of stability
for marketed products used as control articles.
FDA declines to adopt this recommendation. The only stability information
typically included on the labeling of marketed products is the expiration date. The
manufacturer's expiration dating on a marketed product is not adequately precise to
provide data on the strength of the control article used throughout a nonclinical
laboratory study. Lacking precise stability information respecting the control article
could raise doubts concerning whether the test and control articles are comparable.
Furthermore, mixing the marketed product with a carrier or use of the product in a manner
not in accord with its labeling could alter the stability characteristics of the product.
For these reasons, FDA concludes that determination of the stability in accordance with
the procedures in § 58.105(b) still is appropriate for any products used as control
articles.
38. Several comments recommended that FDA revise § 58.105(c) to remove
the current requirement that storage containers be assigned to a test article for the
duration of a nonclinical laboratory study. The comments argued that the requirement is
unnecessary and is inconsistent with the Organization for Economic Cooperation and
Development principles of GLP. One comment alleged that the statement is vague and
questioned whether the provision would permit a storage container that a laboratory
emptied during the conduct of, but before completion of, a study to be destroyed or
reused. The same comment also questioned whether, as the test article is depleted during
the conduct of a study, the provision would permit a laboratory to transfer the test
article into a container smaller than that originally assigned to the article.
FDA does not believe that it would be appropriate to eliminate the storage
container provision in § 58.105(c). FDA advises that the provision simply requires that
each test article storage container be assigned to a test article at the beginning of a
study and remain so assigned until the study is completed, terminated, or discontinued.
The test article may not be transferred to different sized storage containers as a study
progresses, nor may assigned storage containers be destroyed while a study is in progress.
The agency recognizes that it may be inconvenient for laboratories,
especially small laboratories, to devote space to a test article container which is
emptied before a study is completely terminated, or discontinued, or which might be
replaced by progressively smaller containers while a study is in progress. Destroying or
reusing or otherwise substituting for originally assigned, identified test article storage
containers, however, could adversely affect the integrity of the study. FDA established
the current provision because the agency observed a lack of accountability for test
materials, ostensibly due to the very acts proscribed by the regulation, i.e., transfer of
test articles to different sized containers and destruction of empty containers during the
progress of nonclinical laboratory studies.
FDA continues to believe that the requirement concerning assignment of
storage containers is necessary to ensure the integrity of a study. For example, the mere
act of transferring a test article from one storage container to another introduces the
opportunity for contamination of the test article by other laboratory materials or for
mix-ups with other laboratory materials. In addition, during a transfer the test article
would be exposed to air-borne contaminants as well as to moisture, either of which may
compromise the integrity of the test article.
FDA also believes that requiring that containers be assigned to a test
article for the duration of a study is fully consistent with the Organization for Economic
Cooperation and Development principles of GLP. Chapter 2, section 2.3 (Ref. 1, p. 31) of
the Organization for Economic Cooperation and Development document states that
"storage container(s) should carry identification information, earliest expiration
date, and specific storage instructions." Although the Organization for Economic
Cooperation and Development document does not further characterize storage instructions
that the Organization for Economic Cooperation and Development would recommend be included
on containers, FDA concludes that its regulation identifies a "specific" storage
instruction that is necessary to assure the integrity of the test article.
Mixtures of Articles with Carriers
39. Two comments argued that the requirements in § 58.113(a) to determine
the uniformity, concentration, and stability of test and control articles in mixtures is
unnecessarily burdensome for short-term studies. One comment stated that such tests are
not necessary for test articles that are prepared and dispensed on the same day as used in
single-dose acute toxicity tests. The comments suggested that the agency revise §
58.113(a) to require that tests of mixtures of test and control articles need be conducted
only "for studies other than short-term."
Section 58.113(a) requires, for all test or control articles mixed with a
carrier, a determination of the uniformity of the mixture and a periodic analysis of the
concentration of the test or control article in the mixture. In addition, §
58.113(a)(2), as amended, requires a determination of the stability of the test or control
article in the mixture adequate to support time of use. Each of these analyses is
necessary to assure that the test system is exposed to the test or to the control article
in the amounts specifically designated in the protocol for a study. Determination of the
uniformity of a mixture assures that each member of the test system receives the intended
dose of test or control article. Periodic analysis of the concentration of the test or
control article serves as a spot check to assure that the test or control article mixture
has been prepared properly and in accord with the protocol and with applicable standard
operating procedures. Determining the stability of the test or control article in
the mixture helps to determine the period of time during which the test or control article
mixture may be suitable for administration to the test system. FDA believes that knowledge
of the dose of test or control article used in any test is essential for the proper
evaluation of the results of that test. For these reasons, FDA has concluded that the
requirements of § 58.113(a) should continue to apply to short-term tests as well as to
studies other than short term.
As discussed in paragraph 36 of this preamble, however, FDA has decided to
allow facilities and sponsors the flexibility to determine the stability of test and
control articles either before study initiation or through periodic analysis of each batch
according to established standard operating procedures. The agency believes that it is
appropriate to allow similar flexibility with respect to determining the stability of
mixtures of articles with carriers. For this reason, on its own initiative, FDA has
revised § 58.113(a)(2) to allow determination of the stability of test and control
articles in the mixture either before study initiation or through periodic analysis of the
mixture according to established standard operating procedures.
40. One comment recommended that FDA delete § 58.113(a)(1), alleging that
periodic determinations of the test or control article in mixtures is routine and
provisions respecting such determination would more appropriately be included in §
58.35(b)(3).
The comment miscontrues the function of the QAU (see especially paragraphs
12 and 18 of this preamble). Current § 58.35(b)(3), as well as § 58.35(b)(3) as revised
by this final rule assigns responsibility for periodic inspection of laboratory operations
to the QAU. The QAU does not, indeed, under § 58.35(a), the QAU may not conduct any
portion of a study. Rather, it is responsible for assuring that a study is conducted
according to the protocol, the standard operating procedures, and the GLP regulations.
Protocol
41. A comment urged the agency to delete the provision in current §
58.120(a)(14) (final § 58.120(a)(10)) that requires that the protocol for each study
identify the records for the study to be maintained. The comment argued that the
requirement in renumbered § 58.120(a)(10) is redundant to the same requirements in §§
58.33(f), 58.190(a), and 58.195(b).
FDA recognizes that §§ 58.33(f), 58.190(a), and 58.195(b) address
records that the GLP regulations require a testing facility to retain in all events. As
the authorized master plan for a study, however, the protocol should identify all records
of the study to be maintained by the testing facility to inform all study participants
fully of recordkeeping obligations. The agency believes that inclusion of this information
in the protocol is essential to ensure adequate documentation of the conduct of the study.
For these reasons, FDA declines to remove § 58.120(a)(10) from the GLP
regulations.
42. One comment recommended that FDA delete the provision in current §
58.120(a)(16) (final § 58.120(a)(12)) that requires that the protocol for each study
include a statement of the proposed statistical methods to be used in the study. The
comment argued that a determination of the statistical methods used to evaluate data can,
in many cases, be made only after data have been reviewed.
FDA recognizes that circumstances occasionally require a testing facility
to modify the proposed statistical methods for analysis of the data in a given study. Good
scientific practice, however, requires consideration of the statistical analysis of a
study as part of the design of the study to assess whether the objectives of the study can
be met. FDA concludes that the requirement is appropriate.
Conduct of a Nonclinical Laboratory Study
43. Section 58.130(c) provides that materials derived from a test system
for examination or analysis (specimens) are to be identified by test system, study,
nature, and the date of collection, and requires that such identification is to be located
on the specimen container or is to accompany the specimen in a manner that precludes error
in the recording and storage of data. Five comments argued that the requirements under §
58.130(c) for specimen identification are overly restrictive and suggested that management
should be responsible for determining methods for identifying specimens.
The identification requirements specified in § 58.130(c) are designed to
preclude error during the conduct of a nonclinical laboratory study. FDA has reviewed the
requirements and has concluded that the identifying information specified in the
regulation is the minimum information needed to distinguish each specimen from all others
that have been collected in the facility thereby protecting against mixups and permitting
orderly storage of specimens. Such information also shows whether the data collected on
each specimen are assigned to the correct component of the test system.
FDA has always provided flexibility in the methods to be used for
identifying the specimens in that the identifying information can be encoded through, for
example, the use of accession numbers affixed to the specimen with the numbers decoded in
accompanying information (see, e.g., paragraph 205 of the preamble to the final rule (43
FR 60008)). The agency believes that the requirements with respect to specimen
identification are the minimum requirements necessary to prevent mixup of specimens or
lost specimen identity.
44. Two comments disagreed with FDA's proposal to revise § 58.130(d),
which currently requires that records of gross findings for a specimen from postmortem
(necropsy) observations shall, in all cases, be provided to a pathologist during study of
the specimen. The proposed revision provides only that such records "should" be
made available to the pathologist. Four comments supported the proposed change on the
ground that the resulting flexibility allows "blinding" of the pathologist. One
comment suggested that § 58.130(d) be deleted in its entirety or, alternatively, modified
by specifying that the records are to be provided to the pathologist "if required by
the protocol."
FDA established § 58.130(d) in the belief that the provision would
increase the pathologist's ability to describe correctly microscopic findings and to
relate such findings properly with the gross postmortem observations (41 FR 51214). FDA
continues to believe that for most studies it is important for the pathologist to have
available the records of gross findings when examining a specimen histopathologically. The
agency recognizes, however, that for certain nonclinical laboratory studies it may be
appropriate for pathologists to evaluate the histopathological specimens without being
informed of the necropsy findings. The change made in the regulation will permit the study
director, in concert with management, to determine the need for "blinding" in
relation to the specific objectives of the study.
FDA advises that it continues to believe that for most studies it is a
preferred practice not to use "blinding" in histopathological evaluation. For
this reason, the agency is not deleting § 58.130(d) as suggested by one comment. The
alternative phrase "if required by the protocol" suggested by the comment would
serve the same purpose as the modification proposed by the agency. Therefore, the agency
is adopting § 58.130(d) as proposed.
45. One comment on § 58.130(e) requested that FDA clarify the meaning of
the term "automated data collection systems," stating that it is unclear whether
§ 58.130(e) applies to tabulation of source data from "hard" copy by automated
systems.
As discussed in paragraph 7a. of this preamble, hand-recorded data
collected during a study are "raw data." The subsequent entry of these
hand-recorded data into a computer system, for example, by data processing clerks or
through the use of optical readers, does not alter the status of the hand-recorded data as
"raw data." The processing of these data by the computer, e.g., tabulation, is
not "direct data input" and is, therefore, not encompassed by the requirements
of § 58.130(e).
Reporting of Nonclinical Laboratory Study Results
46. Section 58.185(a) requires that a final report be prepared for each
nonclinical laboratory study conducted and specifies the minimum information that shall be
included in a final report. One comment urged that § 58.185(a) should be modified to
require final reports to include the specified information only "where
appropriate" to make the requirements respecting final reports consistent with FDA's
proposal to change § 58.120(a) respecting protocols. Alternatively, the comment urged
that, at the least, § 58.185(a)(8), which requires that any final report shall include a
description of the dosage, dosage regimen, route of administration, and duration, should
be so modified. The comment argued that some of the information required under this
paragraph is not applicable to certain studies involving medical devices.
FDA proposed to change § 58.120(a) in recognition of the fact that
certain of the enumerated items are not necessary for the protocols for all studies. FDA
has carefully reviewed each of the items listed in § 58.185(a) and has concluded that the
information required by this section to be included in a final report for a nonclinical
laboratory study is necessary to evaluate any such study. FDA notes that § 58.185
currently allows certain appropriate flexibilities where specified information is
determined by the laboratory not to be relevant to a study. For example, § 58.185(a)(4)
provides that test and control articles may be identified by "other appropriate
characteristics" and § 58.185(a)(7) includes the term "where applicable."
The agency believes that the information required by § 58.185(a)(8) is applicable to
studies involving medical devices. For example, "dosage" and "dosage
regimen" for devices may be expressed in units used per animal at a designated
frequency of use. "Route of administration" may describe the means by which the
device is used in relation to the animal. "Duration" would pertain to the period
of time the device was tested in the animal. These clarifications should permit
nonclinical laboratory studies on medical devices to be reported properly.
47. Section 58.185(a)(10) requires that each final report of a nonclinical
laboratory study include the name of the study director, the names of other scientists or
professionals, and the names of all supervisory personnel involved in the study. One
comment recommended that FDA revise § 58.185(a)(10) to require identification only of the
study director and of the principal scientists involved in the study.
FDA disagrees with this suggestion. Supervisors play an important role in
the data collection process. They supervise those who perform the procedures, may
recommend or actually provide training, and assure that data collection is carried out in
accordance with the protocol, the standard operating procedures, and the GLP regulations.
The names of all scientists, professionals, and supervisors are needed to assure the
accountability of all of those individuals responsible for the integrity of the study. The
comment did not provide any data or information to support its recommendation to revise §
58.185(a)(10) and the agency concludes that it should retain the current requirement.
48a. Section 58.185(a)(12) requires that the final report of a nonclinical
laboratory study include the signed and dated reports of each of the individual scientists
or other professionals who were involved in the study. Two comments recommended that FDA
revise § 58.185(a)(12) to allow for combined reports signed by the principal scientists.
According to the comments, allowing for such combined reports would be consistent with the
Organization for Economic Cooperation and Development principles of GLP.
The agency does not believe that a combined report from scientists of
different disciplines would be appropriate. Each individual scientist involved in a study
has to be accountable for reporting data, information, and views within his or her
designated area of responsibility. Reports which combine the data, information, and views
of more than one such person would obscure the individual's accountability for accurate
reporting. Furthermore, FDA believes that the comment has misinterpreted the standard that
the Organization for Economic Cooperation and Development established respecting reports
of persons involved in a nonclinical laboratory study. Chapter 2, section 2.3 (Ref. 1, p.
36) of the Organization for Economic Cooperation and Development document provides that
"if reports of principal scientists from co-operating disciplines are included in the
final report, they should sign and date them." It provides further that the final
report should contain the "names of other principal personnel having contributed
reports to the final report." These provisions do not imply that combined reports
would be appropriate. Rather, they support the need for individual accountability. The
Organization for Economic Cooperation and Development provisions are entirely consistent
with the provisions of § 58.185(a)(12).
48b. On its own initiative, FDA is amending § 58.185(b) to provide that
the final report shall contain the dated signature of the study director to conform the
provision to the definition of "study completion date" being added by this final
rule (see paragraph 6 of this preamble).
Storage and Retrieval of Records and Data
49. FDA proposed to revise § 58.190(a) to allow wet specimens and
specimens from mutagenicity tests to be discarded after evaluation and recording. The
agency's proposal was supported by several comments. One comment, however, requested that
the agency clarify the meaning of "mutagenicity tests" as the term is used in §
58.190(a). The comment asked whether, for example, in vitro cell transformation is
interpreted to be a mutagenicity test under this provision.
FDA advises that, for the purpose of § 58.190(a), the agency considers
mutagenicity tests to be those tests designed to assess the capacity of a test or control
article to induce heritable changes in a test system. Accordingly, FDA considers in vitro
cell transformation to be a mutagenicity test as the term is used in the GLP regulations.
50. One comment recommended that FDA further revise § 58.190(a) to assure
that the regulation makes clear that final reports must be retained.
As discussed at length in the preamble to the proposal (49 FR 43534), FDA
intended to exclude from the retention requirements of the GLP regulations specimens that
are relatively fragile or contribute only in a minor way to safety evaluation. FDA did not
intend to change the current requirement that final reports of any nonclinical laboratory
study are to be retained in accordance with § 58.195. To preclude any possible confusion
regarding the requirement that final reports must be retained, FDA is rewording §
58.190(a) to read "all raw data, documentation, protocols, final reports, and
specimens (except those specimens obtained from mutagenicity tests and wet specimens of
blood, urine, feces, and biological fluids) generated as a result of a nonclinical
laboratory study shall be retained."
Retention of Records
51. FDA proposed to delete from current § 58.195(c) the listed examples
of materials that the agency believes need to be retained only so long as the quality of
the preparation affords evaluation. One comment noted that § 58.195(c) should be further
revised to delete wet specimens to be consistent with the proposed revisions in §
58.190(a) (see paragraph 50 of this preamble).
FDA agrees with the comment and in this final rule is conforming §
58.195(c) to revised § 58.190(a). In pertinent part, § 58.195(c) now reads "Wet
specimens (except those specimens obtained from mutagenicity tests and wet specimens of
blood, urine, feces, and biological fluids), samples of test or control articles, and
specially prepared material * * *."
52. Two comments suggested that FDA should specifically provide in new §
58.195(g) that records to be retained under the GLP regulations may be retained as
magnetic media.
Section 58.195(g), which is being added to Part 58 by this final rule,
provides that records respecting a nonclinical laboratory study may be retained as
original records or as true copies such as photocopies, microfilm, microfiche, or other
accurate reproductions of the original records. Magnetic media could qualify as either
"original records" or "accurate reproductions of the original
records." This conclusion is consistent with § 58.3(k), which includes
"magnetic media" within the meaning of "raw data." Consequently, the
agency does not believe that it is necessary to change new § 58.195(g) in order to
achieve the result desired by the comments.
Reference
The following reference has been placed on display in the Dockets
Management Branch (HFA-305), Food and Drug Administration, Rm. 4-62, 5600 Fishers Lane,
Rockville, MD 20857, and may be seen in that office between 9 a.m. and 4 p.m., Monday
through Friday.
1. "Good Laboratory Practice in the Testing of Chemicals,"
Organization for Economic Cooperation and Development Publications, Paris, France, 1982.
Economic Assessment
As announced in the proposal, FDA has examined the economic consequences
of this final rule in accordance with Executive Order 12291 and the Regulatory Flexibility
Act (Pub. L. 96-354). At that time, the agency concluded that the changes would not
constitute a major rule as defined in the Order and that no regulatory flexibility
analysis would be required. The agency also certified that the revisions would not have a
significant impact on a substantial number of small entities. The agency has not received
any new information or comments that would alter its previous determination.
Environmental Impact
The agency has determined under 21 CFR 25.24(a)(10) that this action is of
a type that does not individually or cumulatively have a significant effect on the human
environment. Therefore, neither an environmental assessment nor an environmental impact
statement is required.
Paperwork Reduction Act of 1980
Sections 58.35(b) (1), (3), and (6), 58.63(b), 58.90(c), 58.105(a),
58.120(a), 58.130(e), and 58.190 (a) and (e) of this final rule contain collection of
information requirements. FDA submitted a copy of the proposed rule containing the same
requirements to the Office of Management and Budget (OMB). These collection of information
requirements were approved under OMB Control No. 0910-0203.
List of Subjects in 21 CFR Part 58
Laboratories.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 21 CFR
5.11, Part 58 is amended as follows:
PART 58 -- GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES
1. The authority citation for 21 CFR Part 58 is revised to read as
follows:
Authority: Secs. 306, 402(a), 406, 408, 409, 502, 503, 505, 506, 507, 510,
512-516, 518-520, 701(a), 706, 801, Pub. L. 717, 52 Stat. 1045-1046 as amended,
1049-1053 as amended, 1055, 1058 as amended, 55 Stat. 851 as amended, 59 Stat. 463 as
amended, 68 Stat. 511-517 as amended, 72 Stat. 1785-1788 as amended, 76 Stat. 794 as
amended, 82 Stat. 343-351, 90 Stat. 539-574 (21 U.S.C. 336, 342(a), 346, 346a, 348, 352,
353, 355, 356, 357, 360, 360b-360f, 360f, 360h-360j, 371(a), 376, 381); secs. 215, 351,
354-360F, Pub. L. 410, 58 Stat. 690, 702 as amended, 82 Stat. 1173-1186 as amended
(42 U.S.C. 216, 262, 263b-263n); 21 CFR 5.11.
2. In § 58.1 by designating the existing text as paragraph (a) and adding
new paragraph (b), to read as follows:
§ 58.1 Scope.
* * * * *
(b) References in this part to regulatory sections of the Code of Federal
Regulations are to Chapter I of Title 21, unless otherwise noted.
3. In § 58.3 by removing the phrase "of this chapter" wherever
it appears; by revising paragraphs (c), (d), and (e)(8); by removing and reserving
paragraph (e)(12); by replacing "in section 513 of the act" with "in Part
860" in paragraph (e)(17); by replacing "section 514 of the act" with
"in Part 861" in paragraph (e)(18); and by adding new paragraphs (o) and (p), to
read as follows:
§ 58.3 Definitions.
* * * * *
(c) "Control article" means any food additive, color additive,
drug, biological product, electronic product, medical device for human use, or any article
other than a test article, feed, or water that is administered to the test system in the
course of a nonclinical laboratory study for the purpose of establishing a basis for
comparison with the test article.
(d) "Nonclinical laboratory study" means in vivo or in vitro
experiments in which test articles are studied prospectively in test systems under
laboratory conditions to determine their safety. The term does not include studies
utilizing human subjects or clinical studies or field trials in animals. The term does not
include basic exploratory studies carried out to determine whether a test article has any
potential utility or to determine physical or chemical characteristics of a test article.
(e) * * *
(8) Data and information about a substance submitted as part of the
procedures for establishing a tolerance for unavoidable contaminants in food and
food-packaging materials, described in Parts 109 and 509.
* * * * *
(12) [Reserved]
* * * * *
(o) "Study initiation date" means the date the protocol is
signed by the study director.
(p) "Study completion date" means the date the final report is
signed by the study director.
4. In § 58.31 by revising paragraph (b), to read as follows:
§ 58.31 Testing facility management.
* * * * *
(b) Replace the study director promptly if it becomes necessary to do so
during the conduct of a study.
* * * * *
5. In § 58.35 by removing paragraph (e), by revising paragraphs (a) and
(b) introductory text, (1) and (3), and by adding an OMB number at the end of the section
to read as follows:
§ 58.35 Quality assurance unit.
(a) A testing facility shall have a quality assurance unit which shall be
responsible for monitoring each study to assure management that the facilities, equipment,
personnel, methods, practices, records, and controls are in conformance with the
regulations in this part. For any given study, the quality assurance unit shall be
entirely separate from and independent of the personnel engaged in the direction and
conduct of that study.
(b) The quality assurance unit shall: (1) Maintain a copy of a master
schedule sheet of all nonclinical laboratory studies conducted at the testing facility
indexed by test article and containing the test system, nature of study, date study was
initiated, current status of each study, identity of the sponsor, and name of the study
director.
* * * * *
(3) Inspect each nonclinical laboratory study at intervals adequate to
assure the integrity of the study and maintain written and properly signed records of each
periodic inspection showing the date of the inspection, the study inspected, the phase or
segment of the study inspected, the person performing the inspection, findings and
problems, action recommended and taken to resolve existing problems, and any scheduled
date for reinspection. Any problems found during the course of an inspection which
are likely to affect study integrity shall be brought to the attention of the study
director and management immediately.
* * * * *
(Collection of information requirements approved by the Office of Management and Budget
under number 0910-0203.)
6. By revising § 58.41, to read as follows:
§ 58.41 General.
Each testing facility shall be of suitable size and construction to
facilitate the proper conduct of nonclinical laboratory studies. It shall be designed so
that there is a degree of separation that will prevent any function or activity from
having an adverse effect on the study.
7. In § 58.43 by removing paragraph (e) and by revising the first
sentence of paragraph (c) to read as follows:
§ 58.43 Animal care facilities.
* * * * *
(c) Separate areas shall be provided, as appropriate, for the diagnosis,
treatment, and control of laboratory animal diseases. * * *
* * * * *
8. In § 58.45 by revising the last sentence, to read as follows:
§ 58.45 Animal supply facilities.
* * * Perishable supplies shall be preserved by appropriate means.
9. By revising § 58.49, to read as follows:
§ 58.49 Laboratory operation areas.
Separate laboratory space shall be provided, as needed, for the
performance of the routine and specialized procedures required by nonclinical laboratory
studies.
§ 58.53 [Removed]
10. By removing § 58.53 Administrative and personnel facilities.
11. By revising § 58.61, to read as follows:
§ 58.61 Equipment design.
Equipment used in the generation, measurement, or assessment of data and
equipment used for facility environmental control shall be of appropriate design and
adequate capacity to function according to the protocol and shall be suitably located for
operation, inspection, cleaning, and maintenance.
12. In § 58.63 by revising paragraph (b) and by adding an OMB numbert at
the end of the section, to read as follows:
§ 58.63 Maintenance and calibration of equipment.
* * * * *
(b) The written standard operating procedures required under §
58.81(b)(11) shall set forth in sufficient detail the methods, materials, and schedules to
be used in the routine inspection, cleaning, maintenance, testing, calibration, and/or
standardization of equipment, and shall specify, when appropriate, remedial action to be
taken in the event of failure or malfunction of equipment. The written standard operating
procedures shall designate the person responsible for the performance of each operation.
* * * * *
(Collection of information requirements approved by the Office of Management and Budget
under number 0910-0203.)
13. In § 58.81 by revising the first sentence of paragraph (c), to read
as follows:
§ 58.81 Standard operating procedures.
* * * * *
(c) Each laboratory area shall have immediately available laboratory
manuals and standard operating procedures relative to the laboratory procedures being
performed. * * *
* * * * *
14. In § 58.90 by revising paragraphs (b) and (c) and by adding an OMB
number at the end of the section, to read as follows:
§ 58.90 Animal care.
* * * * *
(b) All newly received animals from outside sources shall be isolated and
their health status shall be evaluated in accordance with acceptable veterinary medical
practice.
(c) At the initiation of a nonclinical laboratory study, animals shall be
free of any disease or condition that might interfere with the purpose or conduct of the
study. If, during the course of the study, the animals contract such a disease or
condition, the diseased animals shall be isolated, if necessary. These animals may be
treated for disease or signs of disease provided that such treatment does not interfere
with the study. The diagnosis, authorizations of treatment, description of treatment, and
each date of treatment shall be documented and shall be retained.
* * * * *
(Collection of information requirements approved by the Office of Management and Budget
under number 0910-0203.)
15. In § 58.105 by revising the first sentence of paragraph (a), by
revising paragraph (b), and by adding an OMB number at the end of the section, to read as
follows:
§ 58.105 Test and control article characterization.
(a) The identity, strength, purity, and composition or other
characteristics which will appropriately define the test or control article shall be
determined for each batch and shall be documented. * * *
(b) The stability of each test or control article shall be determined by
the testing facility or by the sponsor either: (1) Before study initiation, or (2)
concomitantly according to written standard operating procedures, which provide for
periodic analysis of each batch.
* * * * *
(Collection of information requirements approved by the Office of Management and Budget
under number 0910-0203.)
16. In § 58.113 by revising paragraph (a)(2), to read as follows:
§ 58.113 Mixtures of articles with carriers.
(a) * * *
(2) To determine the stability of the test and control articles in the
mixture as required by the conditions of the study either (i) before study initiation, or
(ii) concomitantly according to written standard operating procedures which provide for
periodic analysis of the test and control articles in the mixture.
* * * * *
17. In § 58.120 by revising paragraph (a) and by adding an OMB number at
the end of the section, to read as follows:
§ 58.120 Protocol.
(a) Each study shall have an approved written protocol that clearly
indicates the objectives and all methods for the conduct of the study. The protocol shall
contain, as applicable, the following information:
(1) A descriptive title and statement of the purpose of the study.
(2) Identification of the test and control articles by name, chemical
abstract number, or code number.
(3) The name of the sponsor and the name and address of the testing
facility at which the study is being conducted.
(4) The number, body weight range, sex, source of supply, species, strain,
substrain, and age of the test system.
(5) The procedure for identification of the test system.
(6) A description of the experimental design, including the methods for
the control of bias.
(7) A description and/or identification of the diet used in the study as
well as solvents, emulsifiers, and/or other materials used to solubilize or suspend the
test or control articles before mixing with the carrier. The description shall include
specifications for acceptable levels of contaminants that are reasonably expected to be
present in the dietary materials and are known to be capable of interfering with the
purpose or conduct of the study if present at levels greater than established by the
specifications.
(8) Each dosage level, expressed in milligrams per kilogram of body weight
or other appropriate units, of the test or control article to be administered and the
method and frequency of administration.
(9) The type and frequency of tests, analyses, and measurements to be
made.
(10) The records to be maintained.
(11) The date of approval of the protocol by the sponsor and the dated
signature of the study director.
(12) A statement of the proposed statistical methods to be used.
* * * * *
(Collection of information requirements approved by the Office of Management and Budget
under number 0910-0203.)
18. In § 58.130 by revising paragraphs (d) and (e) and by adding an OMB
number at the end of the section, to read as follows:
§ 58.130 Conduct of a nonclinical laboratory study.
* * * * *
(d) Records of gross findings for a specimen from postmortem observations
should be available to a pathologist when examining that specimen histopathologically.
(e) All data generated during the conduct of a nonclinical laboratory
study, except those that are generated by automated data collection systems, shall be
recorded directly, promptly, and legibly in ink. All data entries shall be dated on the
date of entry and signed or initialed by the person entering the data. Any change in
entries shall be made so as not to obscure the original entry, shall indicate the reason
for such change, and shall be dated and signed or identified at the time of the change. In
automated data collection systems, the individual responsible for direct data input shall
be identified at the time of data input. Any change in automated data entries shall be
made so as not to obscure the original entry, shall indicate the reason for change, shall
be dated, and the responsible individual shall be identified.
(Collection of information requirements approved by the Office of Management and Budget
under number 0910-0203.)
19. In § 58.185 by revising paragraph (b), to read as follows:
§ 58.185 Reporting of nonclinical laboratory study results.
* * * * *
(b) The final report shall be signed and dated by the study director.
20. In § 58.190 by revising paragraphs (a) and (e) and by adding an OMB
number at the end of the section, to read as follows:
§ 58.190 Storage and retrieval of records and data.
(a) All raw data, documentation, protocols, final reports, and specimens
(except those specimens obtained from mutagenicity tests and wet specimens of blood,
urine, feces, and biological fluids) generated as a result of a nonclinical laboratory
study shall be retained.
* * * * *
(e) Material retained or referred to in the archives shall be indexed to
permit expedient retrieval.
(Collection of information requirements approved by the Office of Management and Budget
under number 0910-0203.)
21. In § 58.195 by revising paragraph (c), redesignating paragraph (g) as
paragraph (h), and adding new paragraph (g), to read as follows:
§ 58.195 Retention of records.
* * * * *
(c) Wet specimens (except those specimens obtained from mutagenicity tests
and wet specimens of blood, urine, feces, and biological fluids), samples of test or
control articles, and specially prepared material, which are relatively fragile and differ
markedly in stability and quality during storage, shall be retained only as long as the
quality of the preparation affords evaluation. In no case shall retention be required for
longer periods than those set forth in paragraphs (a) and (b) of this section.
* * * * *
(g) Records required by this part may be retained either as original
records or as true copies such as photocopies, microfilm, microfiche, or other accurate
reproductions of the original records.
* * * * *
§ 58.204 [Amended]
22. In § 58.204 Notice of and opportunity for hearing on proposed
disqualification in paragraph (b) by removing "of this chapter."
§ 58.213 [Amended]
23. In § 58.213 Public disclosure of information regarding
disqualification in paragraph (b) by removing "of this chapter."
§ 58.219 [Amended]
24. In § 58.219 Reinstatement of a disqualified testing facility by
removing "of this chapter."
Frank E. Young,
Commissioner of Food and Drugs.
Otis R. Bowen,
Secretary of Health and Human Services.
Dated: August 10, 1987.
[FR Doc. 87-20375 Filed 9-3-87; 8:45 am]
BILLING CODE 4160-01-M |