Consideration of the Root Causes in Candidate Attrition During Oncology Drug Development

Cancer remained the second-leading cause of death in the United States in 2020, based on the data from the US Centers for Disease Control and Prevention. While there have been lots of money and time devoted to this therapeutic area, the needs from these patients with cancer were still substantial. The fundamental issue is high attrition rate for oncology drugs, which contributes to the higher cost for oncology drug developers. The study for the success rate from first-in-human trials to registration for 10 big pharmaceutical companies in the United States and Europe indicated that the average success rate in all therapeutic fields was about 11% from 1991 to 2000.¹ The success rates varied between different therapeutic areas, whereas oncology drugs had a relatively low success rate, approximately 5%. In other words, only 1 in 20 new chemical entities passed through clinical trials and received an approval from the European and/or the US regulatory authorities. Kola and Landis also studied the reasons for drug attrition during drug development from 1991 to 2000. They discovered that the primary reason for drug attrition changed from inappropriate pharmacokinetics (PK) and low bioavailability (approximately 40%) in 1991 to a lack of efficacy and safety (approximately 60%) in 2000.¹ Kola and Landis concluded 2 strategies that may reduce the rate of attrition. First, in some therapeutic areas with lower success rates (eg, oncology and central nervous system), appropriate animal models and biomarkers have to be carefully chosen during early drug discovery and development stages.¹ For example, a transgenic animal model is more suitable than a xenograft animal model for preclinical studies of oncology drugs. Second, Kola and Landis observed that biologics had a higher success rate to launch from the first-in-human studies, especially in the areas of immunology and cancer, implying that biologics are safer than conventional chemical drugs.¹

Antibody drugs, 1 group of biologics, generally have fewer safety concerns and fewer PK issues.^{2, 3} In general, antibodies possess a few pharmacological characteristics, including high potency, limited off-target toxicity, and a low risk of biotransformation to toxic metabolites.⁴ Thus, the possibility of drug-drug interactions or renal and hepatic impairment on drug excretion is relatively low, which could significantly eliminate a few matters that could potentially result in drug attrition.

On the other hand, Walker and Newell analyzed the data for small molecular cancer drugs on the attrition from 1995 to 2007, indicating that the attrition rate within the oncology field was 82%; however, the attrition rate of kinase inhibitors was 53%.⁵ It is worth noticing that kinase inhibitors were more successful in the high-risk transition from Phase 2 to Phase 3.⁵ In addition, Hutchinson and Kirk concluded that the estimated glomerular filtration rate and vascular endothelial growth factor targeted agents and/or other kinase inhibitors had relative high success rates, especially adjunctly treating with antiangiogenic drugs.⁶ Overall, for small molecular cancer drugs, molecularly targeted drugs demonstrated the potential to reduce attrition rates.

Moreover, Waring et al found that safety and toxicology were the largest sources of drug failure from 4 major pharmaceutical companies from 2000 to 2010, suggesting a lack of safety was the main factor to contribute drug attrition.⁷ The links between physicochemical properties and frequent causes of attrition (eg, preclinical toxicology, clinical safety, and human PK) were also assessed. Waring et al concluded that none of the physicochemical properties correlated with the attrition of the drugs. The work was the first study to investigate the relationship between hydrophobicity and clinical failure, implying the stringent control of physicochemical attributes may not be a key to mitigating attrition in small molecular drug development.⁷

In this study, to understand the root causes of discontinued oncology drugs from 2005 to 2013, the correlated factors were analyzed. Further, a questionnaire was created and disseminated to group leaders in the pharmaceutical industry, the Food and Drug Administration (FDA), and oncology clinicians for first-hand feedback. A few strategies, such as investment on the paradigm-shifting drugs and investigation of biomarkers, were concluded to mitigate attrition. Furthermore, using biomarkers could guide adaptive clinical trials to improve the efficiency of drug discovery and development.

The study sought to assess factors associated with a relatively high attrition rate for oncology drug candidates, which is centric to the problem of how drugs could be adequately designed and how the clinical studies could be employed effectively and efficiently. Recent paradigm shifts in early-stage development and clinical development plans suggest that candidate selection is less influenced by toxicity reduction with more emphasis placed on biologic activity aligned with efficacy expectations. It may suggest that even when the oncology drug candidates had low safety concerns, a lack of efficacy may still be present and impactful. Further, both the attrition cases of antibodies and small molecules increased from 2005 to 2013, which is similar to the fact that the success rate of biologics had leveled out from 2011 to 2013.²⁶ Since efficacy can only be studied by clinical trials, the clinical trials should be unbiasedly designed, and it could be designed in the adaptive ways. For example, with fewer toxicity concerns, the efficacy of biologics could be examined at the early stage of clinical trial to make the process of drug development more efficient and more cost effective. A few options may be considered, such as having Phase 0 to study PK/pharmacodynamics³³ and/or moving the proof-of-concept study to Phase 1.¹⁹ Regardless of what adaptions are chosen, prior to implementing the adaptions, effective communications with regulatory agencies are needed to ensure that the regulatory infrastructure is flexible enough and ready to review these adaptions. Otherwise, these adjustments may incur even more issues during panel review.

In addition, there are unmet needs for a few cancer types in the cancer community. The current advancing technologies can help us identify genomics and/or biomarker alterations, and yet could guide us to design effective clinical trials and further facilitate targeting the right patients. A recent study revealed that the tests from whole genome sequencing for a patient with metastatic colorectal cancer identified more than 2000 genomic alterations.³⁴ Along with the results from transcriptome sequencing, the most differentially expressed genes were the members of 2 proto-oncogene families, FOS and JUN. These results strongly suggested that blocking the reninangiotensin system could render therapeutic benefit.³⁴ Thus, the antihypertensive angiotensin II receptor antagonist irbesartan was considered for drug repurposing to an oncology treatment, resulting in the patient experiencing a dramatic and persistent response. Although this was the successful application of precision medication, it did demonstrate that these molecular-level technologies can accurately aim at the right patients/targets. Similarly, the application of these tools could lead a correct design in the clinical trials, especially for targeting correct subgroup patients.

Considering cancer as a group of complicated and highly heterogeneous diseases, the majority of tumors should provide multiple targets. Therefore, the combination of drugs for oncology treatment is likely required. Given the successful aforementioned example of precision medicine, the genomic-based or biomarker-driven stratification for targeting correct subpopulation of patients can significantly facilitate the outcomes of treatment and prognosis. Additionally, the other key to this successful example was drug repurposing. Based on the fact that to date drugs are skyrocketed in nature, not to mention the failed drugs, the possibility of drug repurposing for oncology treatment should be scrutinized. Drug repurposing can save lots of money and time on drug discovery and development and maximize the capability of a drug. To cope with high demands of combination treatments for the “targeted cancer therapies,” new drug discovery including drug repurposing, companion diagnostics, and adaptive clinical designs with flexible regulatory review should all be comprehensively considered.

The authors declared no competing interests for this work.

No funding was received for this work.