Abstract
Emerging technologies applied in the regulatory field encompass a group of technologies that are used in addition to or in replacement of the standard toxicology studies conducted to support an Investigational New Drug Application (IND) or New Drug Application (NDA). The standard package includes general toxicology studies of various duration, safety pharmacology studies, genetic toxicology studies, and reproductive toxicology studies. New and emerging technologies applied to the regulation of new drugs include the use of novel biomarkers, transfected cells and transgenic animals, and the “omics” technologies (toxicogenomics, proteomics, and metabonomics). These technologies are at various stages of regulatory development and acceptance. For example, the use of transgenic animals have gained acceptance by regulatory authorities to replace a 2-year carcinogenicity assay. Alternatively, the “omics” technologies are not sufficiently advanced to achieve regulatory acceptance as replacements, although these assays have a role early in drug development and they may prove useful as supplements to standard studies. Data from these assays have been used to address specific mechanistic questions in combination with standard toxicology assays.
The incorporation of new technologies into regulatory science is a stepwise process, involving ongoing discussion between industry, academic, and Food and Drug Administration (FDA) scientists. The need to adopt new scientific advances is driven by the desire to improve the safety assessment of new pharmaceuticals and to increase sensitivity and predictiveness of models. The need to improve the safety assessment, and tools to accomplish this task, was described in some detail in the FDA’s Critical Path Initiative (U.S. FDA 2004). Specific areas identified in the Critical Path Initiative included immune toxicity and liver and cardiovascular safety evaluation. This discussion will focus on the scientific review of new technologies and briefly describe how data derived from some new technologies used in toxicology and safety assessment have affected review conclusions. Finally, a brief description, from a regulatory perspective, of emerging “global” technologies will be presented.
Within the Center for Drug Evaluation and Research (CDER), the principal decision-making body on scientific evaluations and decisions involving pharmacology and toxicology issues affecting multiple divisions is the Pharmacology Toxicology Coordinating Committee (PTCC). This committee is comprised of the team leaders of the operating divisions within CDER. A number of subcommittees and working groups have been formed by the PTCC in order to assist with technical matters. To be accepted into pharmacology or toxicology practice in different divisions within CDER, any new and emerging technology will at some time be evaluated by one of the PTCC’s working groups or subcommittees and/or the PTCC.
Perhaps the best example of new technologies affecting regulatory practice is the use of alternative animal models for carcinogenicity assessment. In the past, the standard assay for carcinogen assessment was the 2-year bioassay in rodents (rat and mouse). More recently, an alternative model, usually involving testing of 6 months’ duration, has in some cases been substituted for one of the 2-year assays. The most common alternative models are the p53 (genotoxic compounds), RasH2 (topical products), and TgAC (genotoxic and nongenotoxic compounds) transgenic mouse models. The determination of the appropriateness of the proposed alternative model rests with either the executive Carcinogenicity Assessment Committee (eCAC) or the full CAC depending upon the identified problems. Guidance documents available on the CDER Internet site guidance document page (http://www.fda.gov/cder/guidance/index.htm) are available to assist with the selection of appropriate alternative models, and a general discussion of the models can be found in Pritchard et al. (2002). The PTCC continues to evaluate the appropriateness of the models and study designs for these alternative models.
The PTCC also is developing a working relationship with the Advisory Committee for Pharmaceutical Sciences (ACPS) to assess new technologies. The ACPS, like other FDA advisory committees, is designed as a mechanism through which the Agency can obtain advice from experts outside the Agency. Working with the National Center for Toxicological Research’s (NCTR) Nonclinical Studies Subcommittee (NCSS), expert working groups were formed to examine relevance of biomarkers and the state of the science for vasculitis and cardiotoxicity. The reports and recommendations of the expert working groups will be presented to the ACPS and the PTCC for evaluation.
Another mechanism through which the Agency adopts new technology is through participation in workshops and the review of test methods under consideration of the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM). ICCVAM was established by the National Institute of Environmental Health Sciences (NIEHS) at the direction of Congress in 1997 and now has 15 Federal research and regulatory agencies that participate in the review process. For example, two products that have completed the peer review panel process are Corrositex and the murine local lymph node assay (LLNA). Corrositex is an in vitro test method to examine the dermal corrosivity potential of chemicals. The LLNA is a method for assessing allergic contact dermitis of chemicals, including drugs, is discussed in more detail in CDER’s recently published immunotoxicology guidance document (
Drug developers are encouraged to incorporate new technologies into the scientific evaluation of their product, in order to gain a better understanding of a mechanism of action (i.e., pharmacology) or as an addition to the standard safety assessment (toxicology) at any time in product development. In general, unless the data are derived from test methods that are sufficiently robust, data derived from application of a new technology would most likely be considered supportive rather than as crucial to the safety assessment. The distinction between a pharmacology and toxicology study is at times arbitrary. In general the conduct of the study (GLP [good laboratory practice] versus non-GLP) and the amount of supporting information that needs to be submitted for a pharmacology study is much less than what is generally expected in a study report intended to provide critical safety information (
There are several specific examples of new technologies that have been incorporated into the regulatory review of drugs. In general, these technologies have a fairly extensive research history in multiple laboratories, and were used to provide supportive rather than pivotal data. For example, drug metabolism is usually initially studied in vitro in cell culture systems using cytochrome P450 cDNA expression systems. As an adjunct to these studies, enzyme induction has recently been investigated by using the cytochrome P450 promoter (e.g., the P450 3A promoter) linked to a reporter molecule, e.g., luceriferase. Findings from in vitro metabolism studies have been confirmed with nonclinical and clinical studies.
In some cases, exploratory studies using new technologies have been designed to further investigate a finding observed in a standard toxicology study.
Inbred animal strains with identified mutations and transgenic animals have been used to assess risk. For example, arsenic trioxide was approved by the FDA for the treatment of acute promyelocytic leukemia, and the drug developer relied upon literature information for developmental toxicity assessment. Most of the information on reproductive toxicity of arsenic is based on studies with oral administration, as the greatest concern is from environmental exposure (e.g., drinking water). In a study in which Sploch heterozygote mice were administered 10 mg/kg sodium arsenite, the authors concluded that the introduction of the sploch allelle increased the incidence of neural tube and other malformations (Machado et al. 1999). This and other studies led the FDA to conclude that arsenic trioxide may cause fetal harm if administered to a pregnant woman. In another example, a standard segment II study was conducted to assess developmental toxicity of a small-molecular-weight compound, and the findings were compared to transgenic animals in which the protein target was missing. Similar findings from both studies led to the conclusion that the developmental toxicity findings were due to the pharmacological activities of the drug product. In general, transgenic and imbred animals used in safety assessments are not developed specifically for the drug under study but the assessment relies upon studies available in the scientific literature.
Additional nonstandard studies for genetic toxicity (i.e., studies not part of the International Conference on Harmonization (ICH) core genetic toxicity battery) are often conducted to aid in the assessment of carcinogenic potential of a drug. An example of this is the Muta Mouse assay, which examined lac Z mutation frequency in mouse kidney. However, the CAC questioned the relevance of these data as the tumors are found in rat, not mouse, kidney, thus limiting the usefulness of this alternative assay.
Perhaps the most important emerging technologies are the “global” assays, including pharmacogenomics/ pharmacogenetics, proteomics, and metabonomics. These technologies may be able to cut development time by aiding in the selection of compounds, improve comparability testing for product characterization (http://www.emea.eu.int/pdfs/human/ewp/309702en.pdf), and ultimately provide for “personalized medicine,” providing the right drug tailored for a patient with specific disease characteristics. A workshop was held in May, 2002, between representatives of FDA and the pharmaceutical industry to discuss pharmacogenetics and pharmacogenomics. The workshop agenda and workbook are available from the FDA internet site (www.fda.gov/cder/calendar/meeting/phrma52002/default.htm), and the full report of the workshop has been published (Lesko et al. 2003). Additional FDA comments on this topic have been published (Lesko and Woodcock 2002; Petricoin et al. 2002). Pharmacogenetics and pharmacogenomics are perhaps the furthest advanced of these technologies at the present time. Blood and tumor samples are often collected in clinical trials for genetic or genomic analysis. These technologies have the promise to radically alter the way drugs are investigated and approved. At this time, the Agency has some research and review experience with these emerging technologies, but they are still considered as promising technologies with their full potential yet to be explored.