Adaptive clinical trials for new drugs or treatment options promise substantial benefits to both the pharmaceutical industry and the patients, but complicate resource allocation decisions. In this dissertation, we focus on sequential adaptive clinical trials with binary response, which allow for early termination of drug testing for benefit or futility at interim analysis points. The option to stop the trial early enables the trial sponsor to mitigate investment risks on ineffective drugs, and to shorten the development time line of effective drugs, hence reducing expenditures and expediting patient access to these new therapies. In this setting, decision makers need to determine a testing schedule, or the number of patients to recruit at each interim analysis point, and stopping criteria that inform their decision to continue or stop the trial, considering performance measures that include drug misclassification risk, time-to-market, and expected profit. In the first manuscript, we model current practices of sequential adaptive trials, so as to quantify the magnitude of drug misclassification risk. Towards this end, we build a simulation model to realistically represent the current decision-making process, including the utilization of the triangular test, a widely implemented sequential methodology. We find that current practices lead to a high risk of incorrectly terminating the development of an effective drug, thus, to unrecoverable expenses for the sponsor, and unfulfilled patient needs. In the second manuscript, we study the sequential resource allocation decision, in terms of a testing schedule and stopping criteria, so as to quantify the impact of interim analyses on the aforementioned performance measures. Towards this end, we build a stochastic dynamic programming model, integrated with a Bayesian learning framework for updating the drug’s estimated efficacy. The resource allocation decision is characterized by endogenous uncertainty, and a trade-off between the incentive to establish that the drug is effective early on (exploitation), due to a time-decreasing market revenue, and the benefit from collecting some information on the drug’s efficacy prior to committing a large budget (exploration). We derive important structural properties of an optimal resource allocation strategy and perform a numerical study based on realistic data, and show that sequential adaptive trials with interim analyses substantially outperform traditional trials. Finally, the third manuscript integrates the first two models, and studies the benefits of an optimal resource allocation decision over current practices. Our findings indicate that our optimal testing schedules outperform different types of fixed testing schedules under both perfect and imperfect information. / Ph. D. / Adaptive clinical trials for new drugs or treatment options have the potential to reduce pharmaceutical research and development costs, and to expedite patient access to new therapies. Sequential adaptive clinical trials allow investigators and trial sponsors to terminate drug testing “early,” at interim analysis points, either for benefit or futility reasons. In the first manuscript, we model current practices of sequential adaptive trials, so as to quantify the risk of terminating the development of an effective drug incorrectly. Towards this end, we build a simulation model to realistically represent the current decision-making process. In the second manuscript, we study the financial investment decisions made by the trial sponsor, such as pharmaceutical firms, so as to quantify the impact of interim analyses on a series of performance measures relevant to the firm and the patients. Towards this end, we build a a mathematical optimization model that incorporates elements representing the knowledge gained by decision makers on the drug’s efficacy, which is unknown to them at the beginning of the trial. As a result of our analysis, we obtain an optimal strategy to allocate financial resources in a sequential adaptive trial. In the third and final manuscript, we compare the performance of our optimal resource allocation strategy against the performance of the triangular test, a well-known and widely implemented sequential testing methodology, as measured by the aforementioned performance measures.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/86348 |
| Date | 19 June 2017 |
| Creators | Rojas Cordova, Alba Claudia |
| Contributors | Industrial and Systems Engineering, Bish, Ebru K., Hosseinichimeh, Niyousha, Bish, Douglas R., Ghaffarzadegan, Navid, Triantis, Konstantinos P. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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