While a Phase I clinical study focuses on determining the MTD, Phase II studies evaluate the potential efficacy and characterize treatment benefit for the disease in a convincing manner. The intervention is not presumed to have any therapeutic effect whatsoever.
These studies are performed on larger groups (100 to 300 subjects) and are designed to assess how well the drug works and to continue safety assessments.
Therapeutic doses which were determined during Phase I are administered and patients are monitored by the clinical researcher. Trials are often conducted in a multi-institution setting.
Phase II may be divided into:
- Phase IIA which are pilot clinical trials to evaluate efficacy and safety in selected populations with the disease or condition to be treated, diagnosed or prevented (objectives may be on dose-response, type of patient, frequency of dosing, or other identifiers of safety and efficacy)
- Phase IIB which are the most rigorous trials designed to demonstrate efficacy.
The development process usually fails during Phase II when the drug is discovered not to work as planned or to have toxic effects.
Phase 2 designs
The Phase II design depends on the quality and adequacy of Phase I studies.
A vulnerable aspect of both phases is the type of patient enrolled. Patients in Phase II trials generally have more exclusion criteria than those in Phase III trials. Case series and randomized clinical trial designs have been used.
Single-stage and multi-stage Phase II clinical trial designs are often developed on the basis that one endpoint is of interest.
A commonly used Phase II design is based on the work of Gehan, a version of a two-stage design. Other designs have more stages or a sequential aspect.
Hybrid designs have been used to improve efficiency.
In an update, Gehan reviewed statistical aspects of plans for Phase II cancer clinical trials including:
- A minimum number of patients plan
- A two-stage decision theory approach
- A limited patient accrual plan
- A predictive probability plan
- And a one-sample multiple testing procedure plan.
The author makes recommendations regarding the plan that best fits the needs of the study.
Adaptive clinical trial designs
Adaptive clinical trial designs based on accumulated data at interim have also been used in Phase II clinical trials because of flexibility and efficiency.
This design may allow the researcher to modify or redesign the trial while the study is ongoing.
However, researchers have hesitated in their use. There is:
- Confusion with respect to the definition
- Controversy regarding sample size re-estimation methods
- And logistical barriers in using adaptive designs within existing trial frameworks
In 2010, The FDA classified adaptive designs into “well understood” and “less well understood” categories.
“Well understood” designs
“Well understood” designs have been in use for years with corresponding statistical methods that have been well established and the FDA is familiar with the study designs through the review of submissions using them.
“Less well understood” designs
In the “less well understood” designs, relative merits and limitations have not been completely evaluated, valid statistical methods have not been developed, and the FDA does not have a lot of experience with submissions using the study designs.
Chow, et al. give a broader definition of adaptive design – One that allows adaptations in trial procedures and/or statistical procedures after initiation of the trial without undermining the validity and integrity of the trial.
Adaptive clinical trial designs include:
- An adaptive randomization design
- An adaptive group sequential design
- A flexible sample size re-estimation design
- A drop-the-losers design
- An adaptive dose-finding design
- A biomarker-adaptive design
- An adaptive treatment switching design
- An adaptive-hypothesis design
- A Phase I/II or II/III adaptive seamless trial design
- And a multiple adaptive design
Source: Mahan, V.L. (2014) Clinical Trial Phases. International Journal of Clinical Medicine, 5, 1374-1383.
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