October 09, 2024

Steroidal contraceptives have undergone significant advancements since their inception, particularly in the realm of safety testing and regulatory oversight. The journey began in the 1960s when there were no formal toxicology testing requirements for new drugs, including oral contraceptives. A pivotal moment came with the investigational hormonal steroid ethynerone (MK-665), which caused mammary nodules in beagle dogs during a toxicology study, raising concerns about the potential carcinogenicity of contraceptive steroids in humans. This discovery prompted regulatory authorities, including the FDA, to mandate long-term toxicology studies in beagles and monkeys to assess the risks posed by steroidal contraceptives.

The Changing Guidelines for Contraceptive Testing

In 1987, the World Health Organization (WHO) and other health organizations recognized the need to update safety testing guidelines to reflect evolving scientific understanding. By 1994, Canada’s Therapeutic Products Programme followed suit, revising its guidelines. These updates were critical, as previous long-term animal studies had been mandated without the in-depth knowledge we have today.

Key revisions included:

  • Eliminating the 10-year carcinogenicity test in monkeys and the dog carcinogenicity test.
  • Incorporating detailed pharmacokinetic data for more precise evaluation.

Despite these changes, the updated guidelines-maintained flexibility, allowing authorities to request additional data based on specific cases. This shift reflected the growing recognition that toxicology testing should evolve alongside advances in scientific knowledge.

Phases of Pre-Clinical and Clinical Testing

Pre-clinical toxicology studies remain a cornerstone for the development of new contraceptives, ensuring that a drug is safe before human trials begin. These studies typically involve rodents and monkeys and progress through various phases:

  • Phase I: Single-dose studies in rats and mice, followed by repeat-dose studies in rats and monkeys for a minimum of one month.
  • Phase II & III: Longer-duration toxicology studies alongside genotoxicity tests and reproductive health studies.
  • New Drug Submissions (NDS): Comprehensive testing, including two-year carcinogenicity studies primarily in rats and mice.

These phases help gather vital data regarding the potential toxicological effects of contraceptives, including their impact on reproductive health, and assess the potential risks before widespread human use.

Advanced Pharmacology and Toxicology Studies

Pharmacological testing plays a crucial role in evaluating the efficacy and safety of new contraceptives. These tests assess a drug’s effect on reproductive hormones, neurological, cardiovascular, and immune systems. Additionally, pharmacokinetic data from animal studies are vital to understanding how the drug behaves in the human body.

For comprehensive safety assessments, drugs are tested at various doses, including some significantly higher than intended for human use. This high-dose testing ensures that researchers understand the potential risks at both therapeutic and excessive levels.

Incorporating Computational Methods in Toxicology Testing

Recent advances in computational toxicology have transformed how steroidal contraceptives are evaluated for safety, reducing reliance on long-term animal studies. In silico approaches, such as Quantitative Structure-Activity Relationship (QSAR) models and Read-Across methods, offer efficient, data-driven ways to predict toxicological outcomes. These tools analyse the molecular structures of chemicals and their biological activities to forecast potential adverse effects, allowing for more targeted and predictive safety assessments.

Key computational methods include:

  • QSAR models: These predict the biological activity of compounds based on their chemical structure. For contraceptive steroids, QSAR models help forecast carcinogenicity, genotoxicity, and reproductive toxicity by drawing on existing data from structurally similar compounds.
  • Read Across: This technique leverages existing toxicological data from chemicals with similar structures or properties, helping to predict potential risks for new steroidal compounds without extensive animal testing.

These computational methods are integrated with traditional toxicological approaches, significantly enhancing the efficiency and precision of risk assessments. They allow researchers to identify potential hazards earlier in the drug development process, leading to safer contraceptive products with reduced testing timelines.

Reproductive Health and Carcinogenicity

One of the most critical aspects of contraceptive research is its impact on fertility. Studies are conducted to ensure that once the contraceptive is discontinued, animals (and eventually humans) can return to normal reproductive function. These "return to fertility" studies are essential for assessing the reversibility of contraceptive effects.

Carcinogenicity testing has also evolved. Given that oestrogen and progestogen compounds are known to cause tumours in certain animal species, modern studies aim to limit tumour development while ensuring long-term safety. Computational methods complement these studies by predicting potential carcinogenic effects before long-term animal testing, reducing unnecessary testing while improving safety profiles.

Conclusion: Progress Towards Safer Contraceptives

The evolution of contraceptive safety testing demonstrates the pharmaceutical industry's commitment to ensuring the safety of new products. Through collaboration between global health organizations like the WHO and national regulatory bodies, testing guidelines have become more refined, ensuring that modern contraceptives meet rigorous safety standards. The integration of computational toxicology tools, such as QSAR models and Read-Across methods, has revolutionized the testing landscape, offering more predictive and efficient approaches to safety evaluation.

As science advances, the refinement of these guidelines and methods will bring further improvements, ensuring that contraceptives remain both effective and safe for users worldwide.