ABSTRACT
PURPOSE: To date there has not been an extensive analysis of the outcomes of biomarker use in oncology. METHODS: Data were pooled across four indications in oncology drawing upon trial outcomes from www.clinicaltrials.gov: breast cancer, non-small cell lung cancer (NSCLC), melanoma and colorectal cancer from 1998 to 2017. We compared the likelihood drugs would progress through the stages of clinical trial testing to approval based on biomarker status. This was done with multi-state Markov models, tools that describe the stochastic process in which subjects move among a finite number of states. RESULTS: Over 10000 trials were screened, which yielded 745 drugs. The inclusion of biomarker status as a covariate significantly improved the fit of the Markov model in describing the drug trajectories through clinical trial testing stages. Hazard ratios based on the Markov models revealed the likelihood of drug approval with biomarkers having nearly a fivefold increase for all indications combined. A 12, 8 and 7-fold hazard ratio was observed for breast cancer, melanoma and NSCLC, respectively. Markov models with exploratory biomarkers outperformed Markov models with no biomarkers. CONCLUSION: This is the first systematic statistical evidence that biomarkers clearly increase clinical trial success rates in three different indications in oncology. Also, exploratory biomarkers, long before they are properly validated, appear to improve success rates in oncology. This supports early and aggressive adoption of biomarkers in oncology clinical trials.
Subject(s)
Antineoplastic Agents/therapeutic use , Biomarkers, Tumor , Clinical Trials as Topic , Drug Approval , Markov Chains , Neoplasms/drug therapy , Biomarkers, Tumor/classification , Biomarkers, Tumor/genetics , Breast Neoplasms/chemistry , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Carcinoma, Non-Small-Cell Lung/chemistry , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Clinical Trials as Topic/classification , Clinical Trials as Topic/statistics & numerical data , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Colorectal Neoplasms/chemistry , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Databases, Factual/statistics & numerical data , Drug Approval/methods , Drug Approval/statistics & numerical data , Female , Genetic Markers , Humans , Lung Neoplasms/chemistry , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Male , Medical Oncology , Melanoma/chemistry , Melanoma/drug therapy , Melanoma/genetics , Neoplasms/chemistry , Neoplasms/genetics , Risk , Skin Neoplasms/chemistry , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Stochastic Processes , Time Factors , Treatment FailureABSTRACT
Canada has strengthened intellectual property (IP) protections for pharmaceutical drugs several times over the last 3 decades. This study investigates whether the IP changes had an effect on the market exclusivity time of brand products on the Ontario Drug Benefit (ODB) formulary. We constructed a database that included the first brand approval date for drugs launched between 1974 and 2012, the first ODB listing date of the brand drug, and the first ODB listing date of the generic form of the drug. We then calculated the time of formulary exclusivity to detect any changes in market exclusivity times associated with changes to Canada's IP regimen. There were 595 drugs launched between 1974 and 2012 that were available for analysis. Exclusivity gradually declined from the late 1970s to 1990. Drugs approved in 2004 received 7.6 years of exclusivity, and drugs approved in 2005 received 5 years of exclusivity. Over the time period we analyzed, market exclusivity time of brand drugs experienced marked changes, but we did not detect any systematic effects of Canada's stronger pharmaceutical IP laws on the market exclusivity.
Subject(s)
Insurance, Pharmaceutical Services , Intellectual Property , Databases, Factual , Economic Competition , Humans , OntarioABSTRACT
INTRODUCTION: This study analyzed the risk of clinical trial failure during non-small-cell lung cancer (NSCLC) drug development between 1998 and January 2012. We also looked for factors that impacted clinical trial risk in NSCLC. METHODS: NSCLC drug development was investigated using trial disclosures from http://www.clinicaltrials.gov and other publically available resources. Compounds were excluded from the analysis if they had begun phase I clinical testing before 1998, did not use treatment-relevant endpoints, or if they did not have a completed phase I trial in NSCLC. Analysis was conducted in regard to treatment indication, compound classification, and mechanism of action. RESULTS: Six hundred seventy-six clinical trials that included 199 unique compounds met our inclusion criteria. The likelihood, or cumulative clinical trial success rate, that a new drug would pass all phases of clinical testing and be approved was found to be 11%, which is less than industry aggregate rates. Over half of the biomarkers used in NSCLC have not yet been approved by the Food and Drug Administration in any indication. Biomarker targeted therapies (62%) and receptor targeted therapies (31%) were found to have the highest success rates. The risk-adjusted cost for NSCLC clinical drug development was calculated to be U.S. $1.89 billion. CONCLUSION: Biomarker use alone in this indication resulted in a sixfold increase in clinical trial success whereas receptor targeted therapies did so by almost threefold. Physicians who enroll patients in NSCLC trials should prioritize their participation in clinical trial programs that use biomarkers and receptor targeted therapies.