The existing drug development paradigm was established in 1938 under the Federal Food, Drug, and Cosmetics Act (FFDCA) and still requires animal tests to be conducted in all new drug applications submitted for regulatory approvals. Nevertheless, developers are faced with a 90—95% failure rate for new drugs that pass animal testing when tried in humans.
This paradigm is starting to change as scientists and lawmakers are discussing the adoption of new approach methodologies (NAMs) – already fully integrated in the field of (regulatory) toxicology to assess the safety of chemicals, vaccines, medicines, cosmetic ingredients, and other consumer products – for the evaluation of drug efficacy.
Why new drugs fail?
According to a 2016 study drug attrition rates are due to 4 main reasons:
- lack of clinical efficacy determines between 40% and 50% of failures
- unmanageable toxicity for around 30% of new drugs. Because animal and human physiology are fundamentally different, toxicity problems may not arise in animal models but appear in human clinical trials. The opposite could also be true. Therapies that may benefit people might not make it to market because of toxicity in animal studies, yet that toxicity may be irrelevant to humans.
- poor pharmacokinetic properties cause 10%-15% of drug failures. Drugs are absorbed, distributed, and metabolised differently in different species. This is hard to predict exclusively using animal models
- poor strategic planning: for 10% of drugs, failures were attributed to lack of commercial interest
What are NAMs and how can they help?
NAMs are defined as any technology, methodology, approach, or combination that can provide information on chemical hazard and risk assessment without the use of animals, including in silico, in vitro, and ex vivo approaches. NAMs are not necessarily newly developed methods, rather, it is their application to regulatory decision making or replacement of a conventional testing requirement that is new.
Patient-derived cell models (PDCs) represent a unique tool for the assessment of drug efficacy as they are derived directly from patient tissue and kept in low passage cultures for laboratory testing. PDCs maintain clinically relevant genetic make-up and intra-tumour heterogeneity from the tissue of origin and display similar drug response profiles as observed in the corresponding patients in the clinic. We discussed how PDC models can help reducing new drug attrition rate in a previous blog.
A wind of change
On Sept. 15, 2021, members of the European Parliament overwhelmingly voted in favor of a European Union–wide plan for phasing out the use of animals in research and testing. The plan demands that the European Commission set “ambitious and achievable” objectives and timelines for transitioning to a research system that does not use animals. Highly publicized at the time, the parliament’s call to action epitomized political and societal pressure to eliminate animal testing in Europe.
After initially failing to include the FDA Modernization Act of 2021 in a legislative package, the US Senate passed the FDA Modernization Act 2.0 in September 2022, opening the path for the bill become an enforceable law, possibly this year.
