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

Abstract

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. Kelland summarized discontinued oncology drugs in 2005,8 and Williams published an annual summary for discontinued oncology drugs from 2006 to 2008 and 2010 to 2013.9-15 All 8 published manuscripts listed the discontinued oncology drugs, the medication classes, targeted indication(s), reasons for discontinuation, and the reached phase of clinical trials. In this study, 4 individual factors (ie, latest clinical phase studied, treatment modalities, attrition reasons, and target indication[s], respectively) were categorized for the discontinued drugs in each year. For example, in individual years, discontinued drugs terminated in each clinical phase were grouped, and sequentially the total number of discontinued drugs in each phase was recorded. Similarly, discontinued drugs were grouped in each year by different drug classes, attrition reasons, and indications, respectively, in individual years. The drug classes were classified into “small molecules,” “antibodies” (including monoclonal antibodies, antibody drug conjugates, and vaccines), and “others” (including peptides, proteins, oligonucleotides, gene therapy, and other modalities). The attrition reasons for oncology drugs were categorized in 5 groups: “efficacy,” “toxicity,” “strategic,” “unspecified,” and “PK/formulation.” Finally, the indication for individual discontinued drugs could be designated for 1 or multiple cancer types. If a failed drug with multiple indications were reported, all indications were considered for the specific year for statistical analysis. Thus, for the cancer type analysis, there were more indications than the total number of the discontinued drugs in each year. An analysis of variance (ANOVA) was performed using Microsoft Excel to determine differences among different parameters in each factor. For example, within the factor of the attrition reasons, “efficacy,” “toxicity,” “strategic,” and “unspecified” were the individual parameters. When these parameters were determined to be significantly different from each other, these parameters could be used for further statistical analysis (eg, correlation analysis). Significant differences were declared for P < .05. Sequentially, the parameters as variables were used to understand the correlations within each aforementioned factors (ie, attrition reasons, clinical trial phases, drug classes, and cancer types). When there was no drug categorized for the parameters, 0.2 was used to replace 0 to accomplish the requirement of statistical analysis.16 The principal component analysis and correlation analysis were performed in SAS OnDemand for Academics (SAS Institute). Due to scarcity of some of the parameters, they were either combined into the “others” category in medication classes or included only in the top-ranking parameters as variables in the cancer types. To obtain the up-to-date, insightful information with respect to attrition of oncology drugs, 8 questions were created to retrieve the first-hand responses from experts and clinical professionals. The questions included whether kinase inhibitors and/or biologics could be promising for development of oncology treatment. In addition, whether there are any measures during early drug development stages could effectively prevent attrition of oncology drugs. To secure the information, the questionnaire was disseminated to 11 experts across different sectors of oncology research on July 29, 2022, and there were 5 full responses received from July 29, 2022, to January 4, 2023 (Table 1). Because the survey neither constituted any human subject research, nor demonstrated any risk to compromise the participants’ rights and welfare, after consulting with the Institutional Review Board at the University of Pennsylvania, it was determined that an ethical statement was not required. The responses from individuals were summarized and discussed in the section Summary of Feedback From Survey. The term undruggable was used to describe proteins that may not be targeted pharmacologically. Conversely, a few oncology drugs have been developed to target RAS and MYC proteins. Is there a rationale for considering undruggable targets? Could you also share your opinion regarding the most critical challenge in this field? Could we do more in the preclinical phase (animal, in vitro studies, etc.) prior to the clinical trials for oncology drug development? Please rank the top 3 cancer types for which the drug development has a relatively high attrition rate. Information of discontinued oncology drugs from 2005 to 20138-15 was retrieved and sorted by 4 different factors, whereas the failed supportive drugs were excluded from all analyses. First, discontinued oncology drugs in each year were sorted by clinical phases through which the drugs advanced during drug development (Table 2). There was a trend that the total number of failed drugs increased with time. It was approximately a 2-fold increase in 8 years. When a linear model was used to describe this increasing trend and to project the total number of discontinued oncology drugs to 2023, there were 66 failed oncology drugs, representing a 3-fold increase from 2005. Although this extrapolation had no scientific rationale and likely does not reflect the complicated facets of oncology drug development, an increasing trend could prompt us to understand the cause(s) for drug attrition, which reduces profitability for pharmaceutical sponsors. About half of the discontinued drugs occurred in the clinical Phase 1 trials, and the other half of the discontinued drugs had been approximately split in Phase 2 and Phase 3 studies (Table 2). This indicated that half of the discontinued drugs can be terminated at the early stage of development. This could minimize the financial loss of attrition, compared to attrition at the later stage.19, 20 In addition, the groups between different clinical phases were not the same from 2005 to 2013, based on the results (P = 1.8 × 10−3) of ANOVA. While the principal component analysis and correlation analysis were conducted, there was no high correlation observed, due to small numbers of samples.21 Similarly, no high correlation can be concluded for attrition reasons, medication classes, and cancer types. Table 2 also depicts the number of failed drugs, categorized by individual attrition reasons, including a lack of efficacy, unmanageable safety and toxic issues, strategic considerations, unspecified concerns, and PK or formulation issues. Herein, the strategic considerations included financial concerns, project priorities, and company mergers and acquisitions; and the unspecified concern incorporated the undisclosed reasons. The undisclosed reasons could also be, in part, related to financial considerations. Some pharmaceutical companies decided not to disclose the attrition reasons. Usually, 1 drug was subject to discontinuation with only a single reason. However, there were 3 drugs discontinued with 2 reasons (a lack of efficacy and safety issues). These were AZD-7762 and AZD-2461, terminated in phase 1, and AZD-8055, terminated in phase 2 in 2011.13 All the reasons were included and analyzed by ANOVA, except PK/formulation, due to scarcity. The P value, 1.7 × 10−2, was less than .05, which suggested the attrition reasons were not identical in individual years. Prior to 2009, unspecified concerns were the predominant attrition reasons; however, after 2009, strategic considerations and a lack of efficacy became the major reasons for drug attrition. Excluding unspecified concerns, the majority of the reasons for drug failure was “efficacy” and “strategic,” and the proportion of the corresponding attrition reasons was 29% and 27%, respectively. A lack of efficacy has been concluded in many studies20, 22, 23 to be the primary reason for drug attrition. Interestingly, the annual discontinued drugs from both “strategic” and “unspecified” reasons were more than the failed drugs caused from “efficacy” and “toxicity” reasons between 2005 and 2013, except 2006. This observation could imply that financial elements play a critical role during drug development, and mostly financial elements could drive the drug development plan over sciences and/or technology. For example, when the competitors are aware that they are behind in the drug development pipeline, they will “strategically” discontinue the drug, since profitability of a new drug is the primary concern in the business. While the financial concerns were recognized as a primary factor for drug attrition, this study focused on the discussion of drug design/development, modality selection, preclinical studies, and adaptive clinical trials. Compared to small-molecule drug candidates,24 it has been shown that biologics have lower attrition rates, which may be related partly to the fact that fully human or humanized monoclonal antibodies have reduced toxicity concerns.19 Thus, the relationships between drug classes of the discontinued drugs were studied from 2005 to 2013 (Table 2). During this time period, there were only a few failed drugs that were categorized in the classes other than small molecules and antibodies. These included peptides, proteins, DNA, oligonucleotides, and gene therapy, which were combined into 1 category, “others,” in this study. It was observed that the failed small-molecule drugs significantly increased with time, whereas antibodies had only a modest increasing trend. In addition, antibodies and the “others” class did not have this significant increasing linear trend (P value of slope = .08 and .56, respectively). This indicated that antibodies and “others” exhibited less attrition risk during drug development from 2005 to 2013. While the success rate for biologics was higher than for small molecules during 2012-2014,25 the success rate of new biologics appears to have leveled out from 2011 to 2013, which may reflect capacity levels within the regulatory agency.26 Additionally, the P value, 1.2 × 10−6, from ANOVA also indicated these 3 classes were different. Some failed oncology drugs had only 1 indication, while most of them had multiple indications. In this study, all the indications for these failed drugs were included and studied. Because of the limited number of certain cancer types from 2005 to 2013, 16 different cancer types (eg, mesothelioma, esophageal, neuroendocrine, etc.) were combined to “others.” In addition, unspecified, general, or solid tumors were grouped into 1 category: “unspecified/general/solid.” However, due to a lack of specificity, “others” and “unspecified/general/solid” were excluded from statistical analysis, while these 2 groups had relatively more failed drugs incorporated. Figure 1 illustrates the total number for the targeted indications of the discontinued drugs from 2005 to 2013, and lung cancer was the top indication. Because there were 19 groups (Table S1), which may complicate statistical analysis, only the top 9 cancer types were selected for analysis: lung cancer, breast cancer, colorectal cancer, prostate cancer, lymphoma, leukemia, pancreatic cancer, melanoma, and ovarian cancer. Using ANOVA, the selected 9 individual cancer types were significantly different from each other (P = 1.9 × 10−2). Because cancer is an extremely complex group of diseases, treatment and prognosis for cancer has encountered more challenges than other diseases. For example, when cancer progresses, tumors can evolve to comprise various cell types with distinct genome and cell morphology, let alone the heterogeneity of cancer.27 The heterogeneity of cancer includes interpatient heterogeneity, intrapatient heterogeneity, heterogeneity, and these of cancer, the of and development is not 1 or a few and it may not be the same across the of patients with cancer. Thus, a oncology drug may not be for drug with to the complicated of cancer. kinase inhibitors and inhibitors have been developed in with conventional and to cancer. of these have had promising treatment While attrition of kinase inhibitors an increasing trend from 2005 to 2013 kinase inhibitors could also be for of patients with cancer as a or in with other drugs. the oncology drug have been focused on such as and antibodies, especially have of for various biologics have been used for many and may a of due to the approval and are treatment modality to cancer. However, among all the studied over the a of only 3 therapeutic have been by the there are a few Phase 3 studies, and are for human cancer and In addition, due to the success of for this to therapeutic in oncology has also in the early stage of drug development. In to the drugs, a of a few treatment may all patients with cancer. the physicochemical properties were related to toxicity and bioavailability for small-molecule drugs, the control on physicochemical properties had no on the other requirement of drugs (ie, In addition, the physicochemical properties could of a drug, which could result in either more or less efficacy of the drug, due to the heterogeneity of The efficacy of a drug can only be determined by of clinical could be in the and the physicochemical properties could only for the attributes of and/or the of the relationship is not as as small molecular drugs Thus, to physicochemical properties may not the development for successful In to physicochemical properties of drugs, during drug target is to that the drug has the with the The of is especially for the of cancer. To a for oncology drug development, a target could be a a new target is key to a new drug from clinical trials to a other paradigm-shifting drugs the success of the drug for treatment. The experts also the concerns that there have been a limited number of model in the area, appropriate animal models may be to approximately clinical concern was that any in the preclinical study may or may not clinical failure to in preclinical studies could eliminate the of the drugs, promising results in preclinical models may not to success of clinical trials. 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Using biomarkers can For in the study, this clinical can the efficacy of drug from of patients and secure clinical results to and understand the of of drugs. of the is which can for is most likely to be When the a few strategies have to be for example, the of gene and the to the of a clinical study has to be and prior to the of due to heterogeneity of tumors in the of a drug developed for patients may not be suitable for the trials could be considered to the from clinical studies and reduce the caused by the clinical on the between the top 4 new cancer and colorectal in the United States in for Disease Control and and the top 4 indications and prostate that the discontinued oncology drugs targeted in the of drug development was correlated with of the specific cancer types. the responses from experts regarding the top 3 cancer types with relative high attrition rate was and only prostate cancer the top 4 indications of the discontinued was by 1 This may imply that there could be some cancer for example, pancreatic cancer and which may still be of treatment A lack of of and the to drugs to the target could be the main reasons to the drugs are not to these cancer types. In addition, due to the and of cancer, the of to oncology drug development be factor of attrition. 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