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Nonclinical Laboratories Inspected under Good Laboratory Practices 1987 Final Rule - Good Laboratory Practice Regulations
[Docket No. 83N-0142]
52 FR 33768
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.
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.
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.
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.
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.
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.
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