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Achieve More in Phase I Studies

Published date: 
04/01/2011

Some individuals believe not much has changed in Phase 1 dose escalation studies. A recent review1 that looked at 105 published studies from 1995 to 2004 concluded that there was little consensus in the design of such trials .

The average trial was placebo controlled, double-blind, and included 32 subjects at five dose levels yet with great variation in cohort size. The parallel single-dose design was the most common and most conservative. The use of the crossover designs, both grouped and alternating, were considered more novel approaches.

Since these designs allow the drug to be administered more than once to each subject, they allow more information to be obtained from fewer subjects and, importantly, enable intrasubject comparability at the different dose levels. The use of these crossover designs coincides with industry’s drive to achieve more out of such studies. This newer thinking in the study design and the use of crossover studies is one way that Phase 1 studies can become more efficient.

There has been an emergence of multifunctional protocols or umbrella protocols, particularly in Phase 1. These involve the combination in a single study of the traditional single ascending dose study with the first-in-man multiple-dose tolerance study. Food effect crossover legs have been added as well.

The advantages are that such studies require only one regulatory approval and ethical review, there is consistency in the inclusion/exclusion criteria, and they are quicker to perform. In addition, all parts of the study can be managed by the same project manager and team and be conducted by the same center and the same investigator, which promote operational efficiencies and saves time.

However, these studies require control mechanisms to be in place to assure participant safety when moving from the single-dose to the multiple-dose section of the study; specifically, what data will be available to select the dose regimen for the multiple dose, what decision criteria will be applied, who will apply these criteria, and how this data is assured to be accurate. The key is to be as flexible as possible and use algorithms to clearly define the different possible scenarios.

Figure 2 shows the schematic of such a study design. Traditionally, such dynamic changes during a Phase 1 study were handled by protocol amendments, although the approval of these can restrict the speed of research. With the use of predefined algorithms detailed in the protocol, changes in dose levels and sampling numbers, for example, can be instituted without further regulatory review.

Of course, this must all be explained in clear terms to the study participants in the information sheet and consent form which can result in large and sometimes userunfriendly documents that require a high level of explanation from research staff to ensure that proper informed consent is achieved. Using preapproved consent updates during the study to cover the preplanned changes described by the protocol algorithms is a technique that has to be employed to ensure that informed consent is maintained throughout the study.

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