- INTRODUCTION
The objectives of carcinogenicity studies are to identify tumorigenic potential in animals and assess the risk to humans. Such studies are prompted by concerns from laboratory investigations and toxicology data, particularly for pharmaceuticals used over a patient’s lifetime. The methodologies for these studies were established before current technologies for genotoxic testing and understanding of tumorigenesis by non-genotoxic agents. Recent advancements in genotoxicity, toxicokinetics, and mechanistic studies now aid in preclinical safety assessments and interpreting carcinogenicity study outcomes. Given their resource-intensive nature, these studies should be conducted only when warranted by potential human exposure.
- HISTORICAL BACKGROUND
In Japan, carcinogenicity studies for pharmaceuticals were required if clinical use was expected to last 6 months or more, with considerations for shorter durations. The US mandated preclinical testing for carcinogenic potential for drugs used for 3 months or more. In Europe, regulations outlined requirements for such studies based on duration and type of administration over an extended life span.
- OBJECTIVE OF THE GUIDELINE
The guideline aims to establish the conditions for conducting carcinogenicity studies to prevent unnecessary animal testing and ensure consistency in global regulatory assessments, aligning with accepted scientific standards.
The assessment of the need for carcinogenicity studies involves key factors such as the maximum duration of treatment, concerns from other investigations, intended patient population, prior carcinogenic potential assessments, systemic exposure levels, similarity to endogenous substances, study design, and timing in relation to clinical development.
- FACTORS TO CONSIDER FOR CARCINOGENICITY TESTING
- Duration and Exposure
Carcinogenicity studies should be performed for any pharmaceutical whose expected clinical use is continuous for at least 6 months.
Certain compounds may not be used continuously for over 6 months but can be used intermittently. It is challenging to establish clinically relevant treatment periods for intermittent use concerning carcinogenic potential. Carcinogenicity studies are typically required for pharmaceuticals used frequently for chronic conditions like allergic rhinitis, depression, and anxiety. These studies may also be necessary for specific delivery systems that lead to prolonged exposures. In contrast, infrequently administered pharmaceuticals (e.g., anesthetics, radiolabelled agents) do not require carcinogenicity studies unless there are specific concerns.
- Cause for Concern
Carcinogenicity studies for pharmaceuticals may be recommended when there are concerns about their carcinogenic potential. Key criteria for these recommendations include evidence of prior carcinogenicity in the product class, structure-activity relationships indicating risk, findings of preneoplastic lesions in toxicity studies, and long-term retention of the compound or its metabolites leading to adverse tissue reactions.
- Genotoxicity
Unequivocally genotoxic compounds are presumed trans-species carcinogens, posing a hazard to humans without requiring long-term carcinogenicity studies. However, for drugs intended for chronic administration in humans, a chronic toxicity study lasting up to one year may be necessary to detect early tumorigenic effects.
Assessment of a compound’s genotoxic potential must consider all findings and recognize both the intrinsic value and limitations of in vitro and in vivo tests. Utilizing a test battery reduces the risk of false negatives for genotoxic compounds. Importantly, a single positive result in any genotoxicity assay does not automatically indicate a genotoxic hazard to humans.
- Indication and Patient Population
When carcinogenicity studies are required, they usually need to be completed before application for marketing approval. However, completed rodent carcinogenicity studies are not needed in advance of the conduct of large-scale clinical trials, unless there is special concern for the patient population.
Pharmaceuticals aimed at treating serious diseases may bypass carcinogenicity testing prior to market approval, which allows for faster access to treatments for life-threatening conditions, especially when satisfactory alternatives are unavailable. These studies are, however, expected to be conducted post-approval.
In populations with a life expectancy of less than 2-3 years, long-term carcinogenicity studies are often not required, particularly for oncolytic agents used in advanced systemic disease. However, if a cancer therapy significantly prolongs life, concerns may arise about secondary cancers later. Carcinogenicity studies are typically necessary when these pharmaceuticals are used for adjuvant therapy in tumor-free patients or for extended use in non-cancer indications.
- Route of Exposure
The route of exposure for animals in carcinogenicity studies should, when possible, match the clinical route. If similar metabolism and systemic exposure are shown via different administration routes, studies can proceed with only one route, ensuring that relevant organs for the clinical route receive sufficient exposure to the test material, supported by pharmacokinetic data.
- Extent of Systemic Exposure
Pharmaceuticals applied topically may require carcinogenicity studies, particularly for dermal and ocular routes. Those with low systemic exposure may not need oral route studies unless there’s specific concern for internal organ carcinogenicity. If there’s potential for photocarcinogenic effects from dermal applications, studies generally in mice may be necessary. Ocular route pharmaceuticals may bypass carcinogenicity studies unless significant systemic exposure exists or particular concerns arise.
For different salts, acids, or bases of the same therapeutic moiety, where prior
carcinogenicity studies are available, evidence should be provided that there are no
significant changes in pharmacokinetics, pharmacodynamics, or toxicity. When
changes in exposure and consequent toxicity are noted, then additional bridging
studies may be used to determine whether additional carcinogenicity studies are
needed. For esters and complex derivatives, similar data would be valuable in
assessing the need for an additional carcinogenicity study, but this should be
considered on a case-by-case basis.
- Endogenous Peptides and Protein Substances or Their Analogs
Endogenous peptides and proteins, whether synthesized chemically, extracted from sources, or produced biotechnologically, may require special considerations regarding carcinogenicity studies. Typically, such studies are unnecessary for endogenous substances used at physiological levels, particularly when prior clinical experience exists. However, long-term carcinogenicity studies in rodents should be considered for other biotechnology products based on treatment duration, clinical indications, or patient populations. These studies are particularly important when products show significant biological differences or structural modifications from natural counterparts or result in increased systemic concentrations.
- NEED FOR ADDITIONAL TESTING
The results from animal carcinogenicity studies are often cause for debate regarding their relevance to human safety assessments. Additional research into the mode of action may confirm or deny carcinogenic potential in humans, and mechanistic studies are valuable for evaluating the relevance of tumor findings in animals for human safety.
Supplementary Note
Note 1: Most pharmaceuticals intended for a 3-month treatment are likely to be used for 6 months, as no instances were found where they would be used solely for the shorter duration.
– DR SUBRAMANIAN S IYER
