RESUMO
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.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Aprovação de Drogas , Cadeias de Markov , Neoplasias/tratamento farmacológico , Biomarcadores Tumorais/classificação , Biomarcadores Tumorais/genética , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carcinoma Pulmonar de Células não Pequenas/química , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Ensaios Clínicos como Assunto/classificação , Ensaios Clínicos como Assunto/estatística & dados numéricos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/química , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Bases de Dados Factuais/estatística & dados numéricos , Aprovação de Drogas/métodos , Aprovação de Drogas/estatística & dados numéricos , Feminino , Marcadores Genéticos , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Oncologia , Melanoma/química , Melanoma/tratamento farmacológico , Melanoma/genética , Neoplasias/química , Neoplasias/genética , Risco , Neoplasias Cutâneas/química , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Processos Estocásticos , Fatores de Tempo , Falha de TratamentoRESUMO
We determined the success rate of new drug approval by the US FDA in two breast cancer indications, one of which used a biomarker. This allowed us to assess if biomarkers improved clinical trial risk in breast cancer. We performed a retrospective screening of industry-sponsored drug development programs registered on clinicaltrials.gov from 1998 to 2012 for HER2-positive patients compared to patients that had either failed or had been exposed to anthracycline or taxane, whose first phase I in this indication occurred no earlier than 1998. Compounds not registered on clinicaltrials.gov and studied exclusively outside the US were excluded. Twenty-nine drugs for HER2-positive patients and 28 drugs for anthracycline/taxane-exposed patients met our screening criteria. The overall success rate of new drug development in anthracycline/taxane patients was only 15 %, while in HER2-positive patients it was 23 %. However, HER2-targeted therapies underperformed compared to broad acting agents. The cost for clinical trial testing alone, when adjusted for the risk of failure, for HER2-positive breast cancer patients was $199 million, significantly lower than the cost of $274 million for anthracycline/taxane-experienced patients. The use of a validated biomarker, such as HER2, reduced clinical trial risk by as much as 50 % resulting in cost savings of 27 % in advanced and metastatic breast cancer. However, these data have to be evaluated in a context in which studies combining a novel drug with a novel biomarker not yet recognized by the FDA may actually increase clinical trial risk.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Ensaios Clínicos como Assunto , Aprovação de Drogas/economia , Receptor ErbB-2 , Antraciclinas/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/economia , Neoplasias da Mama/metabolismo , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Análise Custo-Benefício , Feminino , Humanos , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Estudos Retrospectivos , Taxoides/uso terapêutico , Estados Unidos , United States Food and Drug AdministrationRESUMO
PURPOSE: To quantify the clinical trial risk of new drug development in Non-Hodgkin's lymphoma (NHL). Risk estimates for this disease have not been reported before. METHODS: We undertook a retrospective review of clinical trials in (NHL) in four subtypes to compare the success rate with the industry average. Our inclusion criteria required that a drug must initiate its phase I trial in one of the four NHL subtypes between 1998 and June 2008 in the US. In addition, clinical trials of new drug candidates that pertain to four subtypes of NHL were retrieved from clinicaltrial.gov. Drug candidates that did not meet these criteria were excluded from the study. RESULTS: The overall success rate (8-11%) was significantly lower than the industry standard (17%). Overall survival (OS) as a secondary outcome appeared more predictive than primary endpoints that were surrogate, of overall success. Further, targeted therapies appear more successful in these lymphoma sub-types than broad acting drugs. CONCLUSION: Clinical trial risk in NHL, with an 89% failure rate reported here, may be reduced by basing decisions on OS secondary endpoints and biologic drugs.
Assuntos
Ensaios Clínicos como Assunto/métodos , Determinação de Ponto Final/métodos , Linfoma não Hodgkin/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Biotecnologia , Ensaios Clínicos Fase I como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/métodos , Intervalo Livre de Doença , Aprovação de Drogas , Indústria Farmacêutica , Tratamento Farmacológico , Humanos , Imunoterapia , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/mortalidade , Linfoma Folicular/terapia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/terapia , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/terapia , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/mortalidade , Linfoma Cutâneo de Células T/terapia , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Falha de TratamentoRESUMO
PURPOSE: To determine the risk of drug failure during clinical trial testing in Crohn's disease and determine what steps can be taken to improve outcomes. This is the first study to quantify such risk for a single disease. METHODS: Moderate to severe Crohn's disease was investigated by reviewing press releases from 1998 to June 2008. Clinical trial failure causes were classified as commercial or clinical and compared with industry expectations. The risk of failure was also reviewed based on whether the compound was a small molecule drug or a biologic. Lastly, the role of the sponsor was examined, in determining whether the size of the firm involved in a drug program was predictive of the outcome of the study. RESULTS: More than a 120 press releases were reviewed yielding 37 drugs that met our search criteria. The cumulative success rate for drug development in Crohn's disease is 19%, from start to finish of clinical trial testing. New drug approvals are dominated by protein based therapeutics in this indication. Commercial and clinical failures both contributed substantially to the failure rates of new drugs. Phase I clinical testing appeared to offer little risk mitigation with pass rates at 95%. CONCLUSIONS: Funding intended to advance Crohn's disease must take into account the disease specific historical failure rate of drug development in forecasting any reasonable expectation of producing new therapies. As it currently stands, one in five drugs will be successfully approved that enter clinical trial testing in this indication. To manage this risk continued development of biologics over small molecule drugs may be warranted in this disease.
