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DOSE SELECTION FOR CARCINOGENICITY STUDIES CAN BE BASED ON ANY ONE OF FIVE APPROACHES, INCLUDING MAXIMUM TOLERATED DOSE -- ICH DRAFT CONSENSUS GUIDELINE

Executive Summary

High-dose selection for carcinogenicity studies of pharmaceuticals can be derived from one of five approaches, including maximum tolerated dose, according to a consensus draft guideline released for consultation to the regulatory agencies in the U.S., European Community and Japan. The guideline for dose selection for carcinogenicity studies proposes that "any one of several approaches may be appropriate and acceptable for dose selection, and should provide for a more rational approach to dose selection for carcinogenicity studies for pharmaceuticals." The draft guideline, along with other study guidelines in various stages of harmonization, was distributed at the Second International Conference on Harmonization Oct. 27-29 in Orlando ("The Pink Sheet" Nov. 1, p. 13). The approaches are: 1) pharmacodynamic endpoints; 2) toxicity- based endpoints; 3) pharmacokinetic endpoints: a minimum of a 25- fold AUC ratio (rodent: human); 4) saturation of absorption; and 5) maximum tolerated dose. The guideline will be published in the Federal Register for public comment. The ICH document explains that "in the United States, dose selection based on the MTD has traditionally been the only acceptable practice." The guideline notes that "in Europe and Japan, dose selection based on toxicity endpoints or attaining high multiples of the maximum recommended human daily dose (> 100 times on a mg/kg basis) have been accepted." Use of the MTD, which was developed for genotoxic substances, may not be appropriate for non-genotoxic agents, the guideline says. There is concern that "exposures in rodents greatly in excess of the intended human exposures may not be relevant to human risk because they so greatly alter the physiology of the test species [and] the findings may not reflect what would occur following human exposure." During the wrap-up session of the conference, FDA Division of Genetic Toxicology Director Daniel Casciano, PhD, discussed the guideline and provided a summary of what the Expert Working Group on Safety recommended during technical symposia. The expert working group reached agreement on when carcinogenicity studies are required, Casciano said. "It is generally agreed that studies are not required if a product is to be given once or less than three-month's duration," the FDAer said. "There is general agreement that carcinogenicity studies are required if the product is to be given for over six-month's duration." In addition, Casciano said, "there has been agreement that if carcinogenicity data is available in two species, additional studies will not be required if there is a change in the clinical route of administration or if there is a change of the chemical form administered. For example, [from] salt to an acid base." This would be acceptable, "if adequate evidence is provided that there is no significant alteration in metabolic or pharmacokinetic [profiles]." Current requirements in the three regions are different, Casciano explained. "In the United States, carcinogenicity studies are recommended for most drugs, exceptions being drugs intended only for short-term use. In Japan and the EC, carcinogenicity studies are required when there is cause for concern or when long- term clinical use is expected." The expert working group is considering the utility of doing carcinogenicity studies in two rodent species. "In the overall nonclinical evaluation of a chronic-use drug, the rodent bioassay ...was cost[ly] in terms of time, resources and animal uses," Casciano said. "The question is whether one can reduce the usage of animals and reduce the costs of drug development and obtain equivalent information...by doing a two-cell assay instead of a four-cell assay, that is, evaluate one sex in two species or both sexes in one rodent species." The FDAer said that "three important databases are currently undergoing analysis. Adequate data to allow the development of a position is expected in the first part of 1994." Five other consensus draft guidelines were distributed during the ICH conference, including "Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies" and "Toxicokinetics: Guidance for Repeated-Dose Tissue Distribution Studies." The toxicokinetic guideline on systemic exposure emphasizes "the need to integrate pharmacokinetics into toxicity testing, which should aid in the interpretation of the toxicology findings and promote rational study-design development." The guideline provides general principles for consideration and specific aspects of involving toxicokinetics in toxicity testing, such as carcinogenicity testing, and single-dose and repeated-dose toxicity studies. The consensus guideline on repeated-dose tissue distribution studies provides circumstances under which such studies should be considered and describes how they should be conducted. "Repeated- dose studies may be appropriate under certain circumstances based on the data from single-dose tissue distribution studies, toxicity and toxicokinetic studies," the document says. "The studies may be most appropriate for compounds which have an apparently long half- life, incomplete elimination or unanticipated organ toxicity." A holdover from recommendations made at ICH 1, held in November 1991, is the issue of repeat-dose toxicity testing in dogs. At ICH 1, the three regions agreed to delete the LD[50] test from animal testing requirements and to shorten repeat-dose toxicity testing in rodents from 12 to six months ("The Pink Sheet" Nov. 18, 1991, p. 7). The EC and Japan also agreed to reduce repeat-dose testing in dogs from 12 months to six months; however, FDA held off agreeing because its database search showed there were changes between six and 12 months. To resolve the issue, the original plan was for ICH to sponsor a prospective study comparing six and 12-month data. However, the parties could not agree to do this study, so FDA has decided to look at NDA and IND data as it comes into the agency. Results of this analysis may be presented at ICH 3, which will be held Nov. 27-30, 1995 in Yokohama, Japan. ICH working groups are preparing seven draft guidelines, most of which are expected to become consensus guidelines ready for consultation in early 1994. One of the draft guidelines, concerning impurities in new drug substances, was discussed by an ad hoc FDA advisory committee in June ("The Pink Sheet" June 28, p. 11). The committee, in its consideration of a second draft of the guideline, determined that such requirements for qualification of unknown impurities in NMEs should apply to generic drugs and OTC drugs. The fourth and current draft of the guideline (dated Nov. 1) still applies only to new drugs and still calls for "identification of all impurities at or above the 0.1% level." Identification "is expected in batches used in safety studies, clinical studies and as manufactured by the proposed commercial process." Impurities seen in stability studies also should be identified, the guideline adds. The current draft guideline presents a minimum daily intake for an impurity that is different from the levels proposed in the second draft and from the threshold suggested by the advisory committee. "For a drug administered at a dose of greater than 500 mg/day, qualification of impurities which individually would give rise to a dose of more than 500 mcg/day should be considered," the guideline states. "This consideration would take into account factors such as manufacturing reproducibility and/or analytical capability, duration of therapy and route of administration, and any evidence to suggest that low levels of impurities in certain drug or therapeutic classes have been associated with adverse drug reactions in specific patient populations," the draft document says. The impurity guideline contains a decision tree for deciding when and what safety studies should be conducted when an impurity level exceeds the threshold.
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