The Effect of Biomarker Use on the Speed and Duration of Clinical Trials for Cancer Drugs.

BACKGROUND: The purpose of this study was to explore the effects biomarkers have on the duration and speed of clinical trials in oncology. MATERIALS AND METHODS: Clinical trial data was pooled from www.clinicaltrials.gov within the 4 cancer indications of non-small cell lung cancer, breast cancer, melanoma, and colorectal cancer. Heatmaps of clinical timelines were used to display differences in the frequency and timing of clinical trials across trials that used or did not use biomarkers, for all 4 indications. RESULTS: Screening of 8630 clinical trials across the 4 indications yielded 671 unique drugs corresponding to 1224 eligible trials used in our analysis. The constructed heatmaps visually represented that biomarkers did not have an effect on the time gap between trial phases for non-small cell lung cancer and melanoma but did for colorectal and breast cancer trials, reducing the speed of trial timelines. It was also observed that biomarker trials were more often concurrent over shorter periods of time and began later in the timeline for non-small cell lung and colorectal cancers. CONCLUSION: The novel visualization method revealed longer gaps between trial phases, later clinical trial start times, and shorter periods of concurrently run trials for drugs that used biomarkers. The study highlights that biomarker-driven trials might impact drug approval timelines and need to be considered carefully in clinical development plan.

Clinical trial risk in leukemia: Biomarkers and trial design.

This study analyzed the risk of clinical trial failure for leukemia drug development between January 1999 and January 2020. The specific leukemia subtypes of interest were acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Drug development was investigated using data obtained from https://www.clinicaltrials.gov and other publicly available databases. Drug compounds were excluded if they began phase I testing for the indication of interest before January 1999, if they were not industry sponsored, or if they treated secondary complications of the disease. Further analysis was conducted on biomarker usage, drug mechanisms of action, and line of treatment. Drugs were identified following our inclusion criteria for ALL (72), CLL (106), AML (159), and CML (47). The likelihood (cumulative pass rate), a drug would pass all phases of clinical testing and obtain Food and Drug Administration approval, was 18% (ALL), 10% (CLL), 7% (AML), and 12% (CML). Biomarker targeted therapies improved the success rates by three- and sevenfold, for ALL and AML, respectively. Enzyme inhibitors doubled the cumulative success rate for AML. First-line therapy and kinase inhibitors both independently doubled the cumulative success rate for CLL. Oncologists enrolling patients in clinical trials can increase success rates by up to sevenfold by prioritizing participation in trials involving biomarker usage, while consideration of factors such as drug mechanism of action and line of therapy can further double the clinical trial success rate.

Clinical Trial Risk in Chronic Obstructive Pulmonary Disease: The Effects of Drug Class and Inclusion Criteria.

BACKGROUND: This study analyzed the risk of clinical trial failure in chronic obstructive pulmonary disease (COPD) drug development between 1998 and 2015. We investigated elements that influenced clinical trial risk and factors that could improve outcomes during development. OBJECTIVES: This study aims to quantify clinical trial risk for drug development in COPD and factors that affect clinical trial risk. METHODS: Drugs that commenced their phase I testing in this indication from 1998 onwards were retrieved from http://www.clinicaltrials.gov. Compounds investigated had to have an endpoint relevant to the treatment of COPD and be sponsored by the pharmaceutical industry. These compounds were then analyzed based on their mechanism of action and trial inclusion criteria. RESULTS: A total of 766 trials met our screening criteria representing 116 drugs. Of these, 9 gained approval by the US FDA during our study period. The cumulative success rate for clinical development in COPD was 13.4%. Combination therapies of long-acting ß-adrenoceptor agonists (LABA)/long-acting muscarinic antagonists (LAMA) and inhaled corticosteroids (ICS)/LABA had the highest success rates at 80 and 50%, respectively. The risk-adjusted cost for drug development in COPD was USD 532.4 million. CONCLUSIONS: A 13.4% success rate in COPD implies that less than 1 in 7 compounds enrolled into clinical testing would gain FDA approval. LABA/LAMA and ICS/LABA therapies had multiple fold increases in the success rate compared to other drug classes and sizably decreased the risk-adjusted cost of drug development. Moving forward, combination therapies may offer the lowest risk of clinical failure in COPD drug development.

Clinical trial risk in castration-resistant prostate cancer: immunotherapies show promise.

OBJECTIVES: To determine the risk of failure during drug development in castration-resistant prostate cancer (CRPC) and to identify factors that could improve outcomes. METHODS: We investigated CRPC by analysing compounds in phase I to phase III clinical trials between 1998 and April 2011. Drug development failures were classified as medical or commercial and were compared with industry expectations. Compounds were excluded from analysis if their phase I occurred before 1998, if they targeted patients that were did not have hormone-refractory prostate cancer, or if they did not assess outcomes such as overall survival, time to disease progression, or prostate-specific antigen levels. RESULTS: Thorough searches of clinicaltrial.gov and other databases yielded 77 compounds that met the inclusion criteria. The cumulative pass rate for first-line compounds in CRPC was 3% and was far below aggregate industry expectations. In total, there were nearly equivalent numbers of commercial and medical failures. Biological products were found to have had greater relative success than small-molecule drugs and biotechnology firms had been slightly more successful than pharmaceutical firms in this disease indication. Phase III failures were high, despite equally high failures during phase II. CONCLUSIONS: Currently, one in 33 compounds that enters clinical testing will be awarded US Food and Drug Administration approval. This appears to be the highest risk indication investigated to date, based on clinical trial studies alone, with an average cost of $1.411bn to bring a new drug to market when adjusted for risk. Development of radical therapeutics such as immunotherapies may also be warranted instead of classic antineoplastic therapeutics. Given the high clinical trial risk, efforts may have to shift to biomarker and surrogate endpoints to manage future clinical trial risk in prostate cancer.

Clinical trial risk in type-2 diabetes: importance of patient history.

PURPOSE: To determine the risk of clinical trial failure for drugs developed for type-2 diabetes. METHODS: Drugs were investigated by reviewing phase I to phase III studies that were conducted between 1998 and February 2013. The clinical trial success rates were calculated and compared to the industry standard. The drugs were classified into GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors and "Other". The exclusion criteria for drugs in this study: Drugs that were started in phase I studies prior to January 1998 for this indication and drugs whose primary indications were not for the control of blood glucose levels. RESULTS: Data was extracted from clinicaltrials.gov; there were a total of 131 drug candidates that fit our specified criteria, of which 8 received FDA approval. The cumulative success rate for molecules developed for type-2 diabetes is 10%. Small molecules were more successful than biologics. A strong disparity was observed in phase III, with studies that utilised treatment naïve patients having a 40% success rate, compared to an 83% success rate in patients who have had previous anti-hyperglycemic exposure. CONCLUSIONS: 1 in 10 drugs that enter clinical testing in this disease will be approved. The DPP-4 inhibitor class of drugs had the highest success rate of all drug classes with a 63% cumulative success rate; while treatment naïve patients carried the greatest clinical trial risk.

The Effect of Biomarkers on Clinical Trial Risk in Gastric Cancer.

OBJECTIVES: This study examined clinical trial success rates for new drug developments in gastric cancer since 1998. We also examined the clinical trial design features that may mitigate the risk of clinical trial failure. MATERIALS AND METHODS: Clinical trial data was obtained from clinicaltrials.gov. Drugs were included if they entered testing between January 1, 1998 and January 1, 2022 and were excluded if they did not have a completed phase I trial or treated secondary effects of gastric cancer. Transition probabilities were calculated for each phase and compared with industry averages. Success rates were determined based on biomarker usage, drug target, type of therapy, and drug chemistry. RESULTS: Upon screening 1990 trials, 219 drugs met our inclusion criteria. The probability of a drug completing all phases of testing and obtaining FDA approval was 7%, which is below the 11% industry average. The use of biomarkers in clinical development resulted in nearly a 2-fold increase in the cumulative success rate. Biologics also exhibited higher success rates (17%) as opposed to small molecules (1%). This was true even when we compared both drug types that shared the same target. When comparing only receptor-targeted therapies, biologics (62%) continued to outperform small molecules (18%). Similarly, when narrowed down to drugs targeting solely HER2 receptors, biologics continued to prevail (64% vs. 24%). CONCLUSIONS: Implementing biomarkers, receptor-targeted therapies, and biologics in clinical development improves clinical trial success rates in gastric cancer. Thus, physicians should prioritize the enrollment of gastric cancer patients in clinical trials that incorporate the aforementioned features.

Impact of biomarkers on clinical trial risk in breast cancer.

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.

Clinical trial risk in Non-Hodgkin's lymphoma: endpoint and target selection.

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.

Does biomarker use in oncology improve clinical trial failure risk? A large-scale analysis.

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.

The success rate of new drug development in clinical trials: Crohn's disease.

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.

Clinical Trial Risk in Hepatitis C: Endpoint Selection and Drug Action.

Background and Aims. This study analyzed the risk of clinical trial failure of new drugs for hepatitis C between January 1998 and January 2015. Methods. Hepatitis C drug development trials that were in phases I-III of clinical trial testing were obtained from the publicly accessible clinical trial repository and other publicly available databases. Drug compounds were excluded from the study if they began their phase I testing before 1998, if they were not industry sponsored, or if they treated secondary complications of hepatitis C. Clinical trial success rates were analyzed in comparison to industry expectations. Further analysis was conducted on the molecule classifications, the mechanisms of action, and the trial endpoints. Results. One hundred and twenty-three unique drug compounds were found to fulfill the inclusion criteria, eight of which had FDA approval. The overall cumulative pass rate for hepatitis C drugs was 20%, which is double the industry expectation rate. Viral inhibitor small molecule drugs significantly reduced the risk of drug failure during clinical trials compared to other mechanisms of action. Conclusion. On average, one in every five drugs that began clinical testing will be approved for market. Viral inhibitor small molecule drugs are the most promising and hold the least risk.

Biomarker use is associated with reduced clinical trial failure risk in metastatic melanoma.

Given the high morbidity and mortality associated with metastatic melanoma, considerable attention has been paid to identifying potential therapies. Until recently, few therapies have been specifically approved for treating metastatic melanoma. In an attempt to increase clinical trial successes, many therapies are implementing biomarkers for patient stratification. This strategy narrows down the population in an effort to identify appropriate subpopulations that have increased efficacy or fewer safety concerns. However, the addition of a biomarker constitutes an additional risk to clinical development and may therefore increase the overall clinical trial risk. Here, we examine the clinical trial success rate for therapies targeting metastatic melanoma. In addition, we identify the impact that biomarkers have had on the clinical development of this disease.

Biomarkers and receptor targeted therapies reduce clinical trial risk in non-small-cell lung cancer.

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.

Risk of failure of a clinical drug trial in patients with moderate to severe rheumatoid arthritis.

OBJECTIVE: We conducted a systematic review to determine the risk of drug failure in clinical testing with patients with moderate to severe rheumatoid arthritis (RA). METHODS: Therapies for RA were investigated by reviewing phase I to phase III studies conducted from December 1998 to March 2011. Clinical trial success rates were calculated and compared to industry standards. Trial failures were classified as either commercial or clinical failures. The exclusion criteria for drugs in this study: drugs that were started in phase I studies prior to January 1998 for this indication; or studies that enrolled patients who were methotrexate-naive and/or had failed biologic therapy. RESULTS: A search in clinicaltrials.gov and approved drugs for the indication yielded a total of 69 drugs that met the study criteria. The cumulative success rate was determined to be 16%, which is equivalent to the industry standard of 16%. For each phase, the frequency of clinical failures exceeded commercial failures. Clinical studies equally comprised investigations of small molecules and biological agents, but biologics seemed to exhibit a higher success rate overall. CONCLUSION: Clinical trial risk in RA with the 84% failure rate reported here is at par with industry performance and phase II success rate seems to be highly predictive of phase III success.