Clinical utility functions provide Phase 2 trial sponsors with an intuitive metric by which to measure the quality of a selected dose. Such functions reveal the efficacy-to-tolerability ratio of doses under consideration, thereby enabling trials to move forward with doses that are highly effective and which have minimal side-effects. While this is arguably the most popular use of clinical utility functions, they can also help trial designers determine which design ought to be chosen for dose-finding studies. A design which consistently chooses doses with high clinical utility should instill greater confidence than those which often miss this critical target.
Nov 12, 2014 4:04:25 PM
Nov 4, 2014 8:30:00 AM
A key stage of exploratory drug development is implementing a proof-of-concept study to demonstrate the safety of a drug. Given the importance of accurate dose-finding for Phase 3 success, methodological improvements to proof-of-concept studies in Phase 2 can translate into greater likelihood of getting a drug to market.
Oct 30, 2014 10:28:00 AM
During last week’s East Users Group Meeting, Michael Proschan of the NIH and NIAID, gave a presentation on ‘Blinded Adaptations, Permutations and t-tests.’ Given the close connection between adaptive t-tests and adaptive permutation tests, Proschan argued that it is possible to determine the validity of an adaptive t-test from the validity of an adaptive permutation test. Proschan concludes that in adaptive settings, “permutation tests are often valid in adaptive settings, even if blind is maintained.”
Michael's slides are available below. You can also find two of his recent papers on blinded adaptations in the 'Related Items of Interest' section.
Oct 28, 2014 9:30:00 AM
Phase 1 oncology trials typically use either rule-based methods or model-based methods to determine the most acceptable level of dose toxicity with which to move forward in Phase 2. This level of toxicity, called the maximum tolerated dose (or the MTD), is the dose which best balances the medical benefits of a higher dose with the risk of toxicity which comes from subjecting a patient to that same dose. Both rule-based methods and model-based methods determine the MTD by relying on small cohorts of patients who test a set of doses against their dose limiting toxicity.
Sep 18, 2014 10:44:00 AM
When designing clinical trials, many trial designers are advised to keep the trial simple. Prima facie, the keep it simple principle seems like sound advice. There are various logistical uncertainties that arise when implementing a clinical trial, and the more simple a trial – so conventional wisdom says – the easier it is to respond to these uncertainties.
According to Zoran Antonijevic, a Senior Director at Cytel Consulting, there is reason to doubt such conventional wisdom. After all, flexibility is hardly a virtue of a traditional trial design. Simple designs may seem to make it easier to monitor data and report results. However, a flexible design can better address remaining uncertainties in product development. These uncertainties are related to treatment effect, dose selection, or a sub-population that would experience the best benefit/risk from the treatment.
Topics: Oncology, Promising Zone, sample size re-estimation, Enrichment, Cytel Consulting, Efficacy, Interim Analyses, forecasting, optimization, Program and Portfolio Optimization, R&D, Adaptive Clinical Trials
Sep 16, 2014 3:30:00 PM
An FDA Industry Statistics Workshop on September 23 will feature a panel on seamless adaptive designs. Seamless adaptive designs are studies which are able to combine two stages of a clinical trial into one adaptive study, thereby cuting trial costs and reducing study length. The panel will feature Cytel Statistician Lingyun Liu,Lisa Kammerman of AstraZeneca, and Joshua Chen of Merck. The FDA's Sue-Jane Wang will be the featured discussant.
Sep 11, 2014 11:56:00 AM
According to a recent Impact Report from the Tufts Center for the Study of Drug Development, 21% of active clinical trials improve trial success rates and cut operating costs by designing trials with simple adaptive elements like sample size re-estimation and opportunities for early stopping.
Cytel Senior Biostatistician Zoran Antonjevic, who also chairs the DIA’s Adaptive Design Scientific Working Group (ADSWG), says the CSDD's findings come very close to the numbers reported by the ADSWG. The ADSWG recently updated its published findings in a Therapeutic Innovation & Regulatory Science article entitled, ‘Adaptive Design: Results of 2012 Survey on Perception and Use.’ The Survey team, led by Cytel statistician and Senior Director Caroline Morgan, used a variety of source material to report on adaptive designs in clinical trials between 1996 and 2012.
FDA-Industry Session on Cardiovascular Outcome Trials: Mehta on EXAMINE Trial’s Promising Zone Design
Sep 9, 2014 10:41:00 AM
The FDA requires sponsors of new antidiabetic drugs to conduct cardiovascular outcome trials (CVOTs). CVOTs demonstrate that new therapies do not place unacceptable cardiovascular risk on patients suffering from Type 2 diabetes. The average CVOT requires about 5000 patients and takes an average of 5 years to complete. However, a recent white paper by the Cardiac Safety Research Consortium outlines a variety of methods to decrease sample size and study duration, by employing group sequential and adaptive CVOT designs.
Sep 4, 2014 1:10:00 PM
Imagine if we were to count the number of possible reasons that investigators might have for monitoring a biomarker during a clinical trial, and multiply that number by the number of possible adaptive designs available for such investigation. We would naturally assume that whatever the number, it would be rather large. This poses an interesting question for a sponsor of an adaptive clinical trial. Are there any general principles for trial design that may be gleaned from these various possible scenarios?
Sep 2, 2014 11:19:00 AM
As more clinical trials make use of adaptive designs, investors have come to realize that high quality trial designs can result in significant improvements to a trial’s financial risk profile. Regardless of a trial’s eventual success or failure, a well-constructed design provides a drug with the highest possible probability of success while mitigating financial risk.
Aug 28, 2014 8:00:00 AM
Aug 19, 2014 8:48:00 AM
Biostatisticians from Cytel will be delivering a course on adaptive designs at this year’s International Society for Clinical Biostatistics. The course will help attendees develop strategies for interim decision-making, by providing an overview of recent advances in statistical methodology and applying them to case studies in oncology and cardiology
Members of Cytel Consulting are not only expert biostatisticians. In addition, they have practical experience designing adaptive trials for some of the leading biopharmaceutical companies in the industry. They will draw on this experience to cover topics on:
Topics: Adaptive Clinical Trials
Aug 14, 2014 8:00:00 AM
Cytel statisticians are looking foward to attending the Conference of the International Society for Clinical Biostatistics, which will be held in Vienna during the week of August 24th. Members of Cytel will be contributing to four sessions at this conference, including an invited talk on innovation entitled 'Beyond Wild Horses: Developing Innovation at Cytel.' They will also be contributing to a session called Adaptive Designs II, in which they will discuss Backward Image Confidence Intervals, a solution to the problem of parameter estimation at the end of an adaptive trial.
Jul 29, 2014 6:30:00 AM
Adaptive designs are the unsurprising hot topic of this year’s Joint Statistical Meeting, which features over one hundred and thirty sessions on the subject. Statisticians at Cytel look forward to contributing to the dialogue with two papers on adaptive designs, and a workshop for using simulations to benefit from interim data (i.e. for prediction and trial forecasting.) In addition, Cytel Senior Director & Consultant Jim Bolognese has organized a session on making use of adaptive designs to optimize strategy for drug development programs.
In the Ernst & Young 2014 Biotechnology Industry Report, Cytel CTO Nitin Patel writes: "Historically, biotechnology companies haven't fully appreciated the link between trial design and the ability to secure external financing. Yet, adaptive trial designs - which often reduce the risk, time and cost associated with clinical development - can make the math more attractive for investors." [Beyond Borders, p. 20].
Jul 10, 2014 1:53:00 PM
Complexities with identifying suitable test populations in oncology studies contribute significantly to the 60% attrition rate in Phase III trials. Cyrus Mehta, (President of Cytel) has recently authored a paper on ‘Biomarker Driven Population Enrichment for Adaptive Oncology Trials,’ (forthcoming in Statistics in Medicine) which provides an innovative method for using two-stage adaptive designs for population enrichment.
Mehta, et al., are sensitive to the dilemma faced by Phase III trial designers choosing between open and restricted enrollment. Open enrollment allows for a large number of patients, and ensures that all patients who may benefit from a therapy have an opportunity to be involved. By contrast, limiting enrollment is a superior practice for revealing the efficacy of a trial for a targeted population. The proposed method allows for biomarker driven enrichment at interim analysis, meaning that only those subgroups that appear to benefit from therapy need to progress to the second stage of the trial.
Jul 8, 2014 6:00:00 AM
The above graphic is from Cyrus Mehta's slides on 'Adaptive Population Enrichment for Oncology Trials with Time to Event Endpoints.'
Recent advances in precision medicine have meant that therapeutic treatments can now target subsets of a population that are most likely to respond well to treatment. Identification of such subsets largely relies on the presence or absence of particular biomarkers. In order to determine whether or not such biomarkers have predictive diagnostic capabilities, the biomarkers must first be validated as reliable predictive indicators, and thereafter as responding efficaciously to treatment.
Jul 1, 2014 9:47:00 AM
A recent Cytel Seminar on Adaptive Statistical Designs featured a talk by Michael Elashoff (Patient Profiles) on Multivariate Approaches for Risk-Based Monitoring. Elashoff, a former statistical reviewer at the Food and Drug Administration, recommended combining cluster and rules based methods for statistical monitoring. Such adaptive monitoring approaches can substantially reduce the time and expense of data monitoring while ensuring consistently high data quality.
Jun 26, 2014 8:44:00 AM
The rise of biomarker based treatments in oncology has meant a reconceptualization of what constitutes a particular disease. According to the American Society for Clinical Oncology, “We can no longer think of cancer as one disease. Even something like lung cancer could be hundreds of different cancers, each defined by specific molecular characteristics requiring different treatment approaches.”  This means that many oncology trials are slowly moving from large-scale studies of generic populations, towards a system where targeted therapies are offered to smaller sets of patients who all possess certain genetic characteristics.
Nina Selaru of Pfizer Oncology, recently gave a talk at a Cytel Seminar in San Diego in which she described a trial for Xalkori, a therapy for non-small cell lung cancer (NSCLC). Pfizer conducted two Phase 3 trials for Xalkori, one for patients who possessed anaplastic lymphoma kinase (ALK-positive patients) and another for other ‘unselected’ patients. The ALK-positive patients were found to respond very well to treatment. Unfortunately, the ALK-positive patients also displayed certain characteristics not present in the other patients: they were younger, non-smokers who displayed signs of adenocarcinoma. There was concern that these characteristics were driving the efficacy of Xalkori.
Jun 5, 2014 9:37:00 AM
In the US, cancer is the most common cause of death after heart disease, accounting for nearly 1 of every 4 deaths . Tackling the immense burden of this disease, researchers are currently investigating an estimated 900 novel cancer agents in over 6,000 clinical trials . Unfortunately, the clinical success rate remains low, and failed trials amount to billions of dollars invested, while providing little direct benefit to patients. Such failures also discourage patients from participating in the testing of novel treatments: Currently, less than 2% of cancer patients enroll in clinical trials .
May 16, 2014 2:48:00 PM
Cytel Consulting's Zoran Antonijevic
The key focus of precision medicine is identification of patients who would most benefit from a treatment. Proper enrichment of patient population greatly improves the probability of regulatory approval as well as product differentiation through improved efficacy and safety. Greater product differentiation leads to greater market access, as reimbursement is now a key driver to commercial success.