Phase II clinical trials: Does the treatment work?

Phase II clinical studies represent a critical point in determining drug costs, and phase II is a poor predictor of drug success: >30% of drugs entering phase II studies fail to progress, and >58% of drugs go on to fail in phase III.

Once the initial safety of the study drug has been confirmed in Phase I trials, Phase II trials are performed on larger groups (20-300) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects.

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Some Phase II trials are designed as case series, demonstrating a drug’s safety and activity in a selected group of patients. Other Phase II trials are designed as randomized clinical trials, where some patients receive the drug/device and others receive placebo/standard treatment. Randomized Phase II trials have far fewer patients than randomized Phase III trials. Human clinical trials for drug development traditionally progress from small toxicity trials in healthy volunteers (phase I) to proof-of-concept and dose-finding trials in somewhat larger groups of patients with the target condition (phase II), and finally to randomized trials to further delineate clinical efficacy, outcomes, and adverse events in large groups of patients (phase III). The timeframe for passage of a therapeutic agent through clinical testing for Food and Drug Administration (FDA) marketing approval is approximately 12 years, with costs now estimated from $1 billion to $1.8 billion dollars. Adaptive clinical trial design has been proposed as a way to reduce the costs of phase II testing by providing earlier determination of futility and prediction of phase III success, reducing overall phase II and III trial sizes, and shortening overall drug¬†development time. Phase II trials face many challenges due to small sample size and choice of study design. In addition, the relatively short duration of phase II trials makes it difficult to identify long-term side effects and outcomes.

Adaptive trials are a proposed way to shorten clinical trial phases, reduce the number of patients needed for enrollment, better predict later drug success, and reduce drug development costs. Criticisms of ADs have included increased risks of falsely detecting treatment effects (type I errors), premature dismissal of promising therapies as falsely ineffective (type II errors), statistical challenges and bias, and operational bias. Use of ADs has been limited due to lack of inadequate information regarding completed adaptive trials, a lack of practical understanding of how to implement an adaptive trial, and worries about excessive regulatory scrutiny and nonapproval. To date, analysis of AD trials gives conflicting results with regard to their effects on study size and duration.

Phase II proof of concept (POC) (IIa) and dose-finding (IIb) studies represent major challenges in drug development. Prolonged development times delay effective therapies from reaching patients in need and adversely affect industry goals of decreasing time to market. Biomarkers including magnetic resonance imaging, cerebrospinal fluid tau and amyloid beta, and amyloid positron emission tomography have been considered as alternative outcomes to clinical measures. None of these is yet validated. Population enrichment is another possible solution to POC studies. More rapid progression to prespecified milestones can be achieved by enriching the population with risk factors. Conclusions based on enriched populations must be extrapolated with caution. Clinical measures with greater sensitivity than standard trial instruments might represent another strategy applicable to POC studies. Adaptive dose-response designs are being considered as a means of shortening phase IIb studies and creating a seamless interface with phase III.

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Since Phase I trials are usually performed in healthy volunteers, Phase II is the first stage of the drug development process, in which the new drug is tested in patients. The aim of Phase II trials is to find out if the new drug is effective in patients through hypothesis testing and at what dose the balance between efficacy and safety is optimal. The number of patients in these trials range from around thirty to a couple of hundreds, and they usually do not last longer than 2 years[1]. In these trials usually a new treatment is compared to placebo, sometimes also to an already existing treatment or a placebo treatment. In Phase II oncology trials all patients receive the same dose, while in other trials participants are randomly assigned to different treatment groups. These groups may get different doses or get the treatment in different ways to see which provides the best balance of safety and efficacy. In non- drug development there are typically 2 types of trials in Phase II:

  • Proof-of-concept trial (Phase IIa): Testing a high dose and a control, often placebo
  • Dose-Finding trials (Phase IIb): If the proof-of-concept trial is positive a dose-finding trial is performed testing multiple doses and a control in a parallel groups setting.

If the new treatment is found to be equally or more effective than the existing treatment, then the study progresses to Phase III trials, where the drug or treatment is tested on more individuals. The failure of a drug in Phase II trials mainly occurs when it is discovered that the drug has some toxic side effects that were not observed in Phase I or failed to show sufficient efficacy for the medical condition under question.

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