New simulator touts adaptive trial savings

The US Food and Drug Administration (FDA) recently announced it will begin providing guidance for the pharmaceutical industry on the use of adaptive research - which could cut the duration and ultimately the cost of clinical trials by one third - normally it takes at least six-to-nine months between phases while approval and drug manufacturing processes are completed. Any time savings are therefore very important as the industry's R&D spending reached an all-time high of $40bn (€30.3bn) in 2006, while new drug approvals dropped to an eight-year low of 18, and it is expected that the industry will embrace the use of new adaptive methods wherever possible. In anticipation of this, Tessella launched its 'Seamless Phase 2/3 Simulator' at the recent Clinical Trials Congress in London - the first of its kind in the industry. A seamless trial is a type of adaptive trial that involves what would normally be two, consecutive, separate clinical trials being run back-to-back without a pause. Broadly the same protocol is used for both stages, with some limited adjustments made at the end of the first stage based on the results obtained so far. Such an approach is not always appropriate, however, as there will be no opportunity to re-design the protocol for phase III based on the data accumulated in phase II, so in order to allow one to take place, regulators will need to be convinced that the risk of a re-design being required will be low, although there are a number of situations where this risk is likely to be acceptable or even preferable to the alternative, such as when there is already approval for a different indication, or in areas of unmet need or orphan status. In addition, while working out cheaper in the long-run, embarking on a seamless trial will be initially more expensive than doing one phase on its own, as more compound must be manufactured and more investigating centres may be required at the outset, so companies want to be sure of the risks involved in making such an upfront investment. Tessella's simulator has been designed to help sponsors and regulators out with some of these issues. It works by making upfront calculations to determine the richness of a design and produces a range of scenarios simulating how a drug might behave based on the design and predicts the chances of the success or failure of the trial in each scenario. "Out of the top ten pharma firms, we have two that are evaluating the simulator aggressively, two that are dipping their toes in the water, two that are waiting to see what kind of demand there may be for such a system, one that has a copy and one that is developing its own version - the other two I'm not sure of,"​ Tom Parke, Tessella's head of Clinical Trials Solutions told Outsourcing-Pharma.com. According to Parke, there are six ways of approaching a trial in an adaptive way - four that have been used for a long time and two that have only recently beginning to be accepted by the FDA - and one of these involves the use of simulation. The first adaptive method is used in Phase I where patients usually begin on low drug dosages for safety reasons and these can then be increased as appropriate. The second is an "ad-hoc adaptive" approach, where an assessment takes place part-way through the trial to look at how things are going and adjust such things as the entry criteria, dosing, endpoint etc. Exactly what is going to be adjusted does not have to be decided up front as this approach is not taken in trials that will be used for approval purposes. The third method is called "group sequential" and is used, usually during Phase II or II, to decide whether to continue with a trial or not. The fourth uses stratification and is used in Phase II to modify the randomisation if it is required in order to enable an adequate subpopulation analysis, for example. More recently the "dose responsive" adaptive approach is being used in Phase I-II trials. This involves looking frequently at trial data as it runs and adjusting the randomisation to favour the dose, in order to provide enough efficacy for the drug to be clinically viable. This allows patients to be started on a greater range of doses which are then narrowed according to the preliminary data. The sixth and final approach is also new and is like the "adhoc adaptive" method, but because it is used in Phase II-III and counts towards regulatory approval, sponsors must outline up front what changes they intend to make and the FDA sets specific rules that must be followed. Such trials can also be seamless, meaning you can move from Phase II to Phase III without stopping.