Costs and Causes of Oncology Drug Attrition With the Example of Insulin-Like Growth Factor-1 Receptor Inhibitors.

Importance: The development of oncology drugs is expensive and beset by a high attrition rate. Analysis of the costs and causes of translational failure may help to reduce attrition and permit the more appropriate use of resources to reduce mortality from cancer. Objective: To analyze the causes of failure and expenses incurred in clinical trials of novel oncology drugs, with the example of insulin-like growth factor-1 receptor (IGF-1R) inhibitors, none of which was approved for use in oncology practice. Design, Setting, and Participants: In this cross-sectional study, inhibitors of the IGF-1R and their clinical trials for use in oncology practice between January 1, 2000, and July 31, 2021, were identified by searching PubMed and ClinicalTrials.gov. A proprietary commercial database was interrogated to provide expenses incurred in these trials. If data were not available, estimates were made of expenses using mean values from the proprietary database. A search revealed studies of the effects of IGF-1R inhibitors in preclinical in vivo assays, permitting calculation of the percentage of tumor growth inhibition. Archival data on the clinical trials of IGF-1R inhibitors and proprietary estimates of their expenses were examined, together with an analysis of preclinical data on IGF-1R inhibitors obtained from the published literature. Main Outcomes and Measures: Expenses associated with research and development of IGF-1R inhibitors. Results: Sixteen inhibitors of IGF-1R studied in 183 clinical trials were found. None of the trials, in a wide range of tumor types, showed efficacy permitting drug approval. More than 12 000 patients entered trials of IGF-1R inhibitors in oncology indications in 2003 to 2021. These trials incurred aggregate research and development expenses estimated at between $1.6 billion and $2.3 billion. Analysis of the results of preclinical in vivo assays of IGF-1R inhibitors that supported subsequent clinical investigations showed mixed activity and protocols that poorly reflected the treatment of advanced metastatic tumors in humans. Conclusions and Relevance: Failed drug development in oncology incurs substantial expense. At an industry level, an estimated $50 billion to $60 billion is spent annually on failed oncology trials. Improved target validation and more appropriate preclinical models are required to reduce attrition, with more attention to decision-making before launching clinical trials. A more appropriate use of resources may better reduce cancer mortality.

Integrative Management of Pancreatic Cancer (PDAC): Emerging Complementary Agents and Modalities.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. The standard first-line treatment for PDAC is gemcitabine chemotherapy which, unfortunately, offers only limited chance of a lasting cure. This review further evaluates the hypothesis that the effectiveness of gemcitabine can be improved by combining it with evidence-based complementary measures. Previously, supported by clinical trial data, we suggested that a number of dietary factors and nutraceuticals can be integrated with gemcitabine therapy. Here, we evaluate a further 10 agents for which no clinical trials have (yet) been carried out but there are promising data from in vivo and/or in vitro studies including experiments involving combined treatments with gemcitabine. Two groups of complementary agents are considered: Dietary factors (resveratrol, epigallocatechin gallate, vitamin B9, capsaicin, quercetin and sulforaphane) and nutraceutical agents (artemisinin, garcinol, thymoquinone and emodin). In addition, we identified seven promising agents for which there is currently only basic (mostly in vitro) data. Finally, as a special case of combination therapy, we highlighted synergistic drug combinations involving gemcitabine with "repurposed" aspirin or metformin. We conclude overall that integrated management of PDAC currently is likely to produce the best outcome for patients and for this a wide range of complementary measures is available.

Pancreatic Cancer (PDAC): Introduction of Evidence-Based Complementary Measures into Integrative Clinical Management.

The most common form of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which comprises some 85% of all cases. Currently, this is the fourth highest cause of cancer mortality worldwide and its incidence is rising steeply. Commonly applied clinical therapies offer limited chance of a lasting cure and the five-year survival rate is one of the lowest of the commonly occurring cancers. This review cultivates the hypothesis that the best management of PDAC would be possible by integrating 'western' clinical medicine with evidence-based complementary measures. Protecting the liver, where PDAC frequently first spreads, is also given some consideration. Overall, the complementary measures are divided into three groups: dietary factors, nutraceutical agents and lifestyle. In turn, dietary factors are considered as general conditioners, multi-factorial foodstuffs and specific compounds. The general conditioners are alkalinity, low-glycemic index and low-cholesterol. The multi-factorial foodstuffs comprise red meat, fish, fruit/vegetables, dairy, honey and coffee. The available evidence for the beneficial effects of the specific dietary and nutraceutical agents was considered at four levels (in order of prominence): clinical trials, meta-analyses, in vivo tests and in vitro studies. Thus, 9 specific agents were identified (6 dietary and 3 nutraceutical) as acceptable for integration with gemcitabine chemotherapy, the first-line treatment for pancreatic cancer. The specific dietary agents were the following: Vitamins A, C, D and E, genistein and curcumin. As nutraceutical compounds, propolis, triptolide and cannabidiol were accepted. The 9 complementary agents were sub-grouped into two with reference to the main 'hallmarks of cancer'. Lifestyle factors covered obesity, diabetes, smoking, alcohol and exercise. An integrative treatment regimen was devised for the management of PDAC patients. This involved combining first-line gemcitabine chemotherapy with the two sub-groups of complementary agents alternately in weekly cycles. The review concludes that integrated management currently offers the best patient outcome. Opportunities to be investigated in the future include emerging modalities, precision medicine, the nerve input to tumors and, importantly, clinical trials.