Potential for a Global Historical Control Database for Proliferative Rodent Lesions

The authors of “Best Practices for Use of Historical Control Data of Proliferative Rodent Lesions” (Keenan et al. 2009), in agreement with available regulatory guidance, support the use of the concurrent study control group(s) as the primary source of data for determination of biologically relevant proliferative tissue responses. Historical control data (HCD) may be used along with concurrent study control group responses when interpreting the incidence range for a specific change in a study. However, approaches for obtaining HCD across studies and between organizations, individuals, and institutions differ. Some organizations may use HCD from a database composed of animal data that have been derived from studies conducted by that organization. If constructed and maintained appropriately, such a database would provide the most comparable data (Keenan et al. 2009). Other industry and most government organizations, lacking such a database, rely on externally generated HCD from outside sources, which prompted our proposal for a global historical control database.

Our review of current practices concerning the use of HCD suggests that the establishment of an easily accessible, well-maintained, and comprehensive global database for HCD may be an effective method to increase uniformity in the use and application of HCD by the global professional community. To improve the scientific strength of HCD used by the broad professional community, this proposed comprehensive global database would use defined criteria for submission of study data (Keenan et al. 2009). This would include a standardized process for the acquisition and validation of data, histopathologic diagnoses, and diagnostic criteria based on internationally established standardized nomenclature (International Harmonization of Nomenclature and Diagnostic Criteria: INHAND and goRENI at http://www.goreni.org/) as well as a stringent peer-review process. These criteria for the generation of strong and scientifically sound HCD have been successfully applied for decades by existing institutions generating HCD such as the Registry of Industrial Toxicology Animal Data (RITA) and the National Toxicology Program (NTP) databases.

We envision a database that is user friendly and searchable by the parameters most consistent with those of the study under evaluation such as study design and duration, vehicle and route of exposure, species, strain, sex, and age of study animals. Study data submission to, and retrieval from, the global historical control database would follow established formal protocols to prevent inappropriate use and interpretation of HCD (Keenan et al. 2009).

Initially, it may be necessary to limit the study data to rodent proliferative lesions. As our review of the literature has shown, factors impacting tumor incidences generally include the following: the study design and duration; the species, strain, sex, age, body weight, and survival time of the animals; the animal supplier, diet, caging type, housing protocol, and number of animals per cage; the environmental conditions, the vehicle, and the route of exposure; and the necropsy and slide preparation techniques, histomorphologic diagnostic criteria and terminology, and pathology peer-review process (Keenan et al. 2009). An example of some of the more important parameters that should be matched when using a global database include the study design and duration, vehicle and route of exposure, species, strain, sex, and age of study animals. In addition, HCD are more comparable if obtained within five years of the study under evaluation. Therefore, individual animal and study data are an important component of the submission process to the proposed global database.

The existing RITA and NTP databases for HCD are of high scientific quality but are limited in the number of rodent strains represented (Morawietz, Rittinghausen, and Mohr 1992; http://ntp.niehs.nih.gov). Moreover, RITA is a privately funded European database and not universally accessible. For RITA membership, an annual maintenance cost must be paid, and submission of study data can be time consuming. Utilizing the model established by RITA, the North American Control Animal Database (NACAD) project attempted to establish a database in North America of neoplastic and proliferative lesions from control animals in carcinogenicity studies (Keenan et al. 2002). However, this database was not continued mainly due to global economic changes, which undermined consistent, long-term financial support. As NACAD has shown, a major challenge to creating the proposed global database for HCD is to secure the resources required for its establishment and maintenance.

Presently, large companies and well-financed institutions may have access to HCD through their company-owned historical control databases or to the databases of large Contract Research Organizations (CROs). A number of companies in Europe and the United States belong to RITA. It may be difficult to convince these companies of the overall advantages that a globally accessible database for HCD may bring to the larger scientific community. In addition, there is a perception among some companies that an in-house proprietary HCD provides the competitive advantage of facilitating a more rapid passage of a prospective product through the regulatory process. Such a mind-set may further limit the willingness of some companies to support development of a global database.

Whether or not the proposed database is established, regulated products will continue to be approved utilizing currently available, often inconsistent HCD from public or private databases and the published literature. Recognizing government agencies as stakeholders in the scientific discussion concerning HCD, their involvement either individually or in collaboration with industry and professional scientific organizations may be considered in searching for support of a globally accessible database. Government agencies could contribute to a global database with information extrapolated from control data submitted to the agency for review. Such a database could be similar to publically maintained databases currently available through Web sites such as the one provided by Charles River. However, many challenges lie ahead concerning the costs to support the infrastructure, maintenance, and administration of a global database for HCD.

In conclusion, the concurrent control groups are the primary source of data for determination of biologically relevant responses. When HCD are needed to aid review of the concurrent control data obtained by a laboratory, then a historical control database composed of data from studies conducted by that laboratory is preferred. When such a database is not available, then a global database could be used by matching important study parameters described above. Access to the same HCD of a proposed global database by all stakeholders of the scientific community will contribute to the scientific confidence in determining the significance of tumor incidences in studies submitted for regulatory review or reviewing trends in tumor biology. In this respect, a global database that provides information on proliferative lesions in the standard organs and tissues typically reviewed in chronic toxicology and oncology studies from various rodent strains under documented scientific conditions will be beneficial to both the industry and the regulatory agencies.