Clinical trial phases – Phase 3

Clinical trial phases - Phase 3 1 Medicine Made Easy Research
Phase III trials are the full scale evaluation of treatment and are designed to compare efficacy of the new treatment with the standard treatment. These are the most rigorous and extensive type of scientific clinical investigation of a new treatment.

This is the “pre-marketing phase” of clinical trials.

These are usually the most expensive and time-consuming of the trials. The trials may be difficult to design and run.

Large groups (100 to 3000 subjects) are recruited and trial designs have included:

  • Randomized controlled trials (parallel design)
  • Uncontrolled trials (single treatment)
  • Historical controls
  • No-randomized concurrent trials
  • Factorial designs
  • And group sequential designs.

Patients are monitored by the clinical researcher and personal physician.

Phase III clinical trials may be divided into Phase IIIA which are trials done after efficacy of the therapy is demonstrated but before regulatory submission of a New Drug Application (NDA) or other dossier and Phase IIIB which are conducted after submission of an NDA or other dossier but before approval and launch.

During the 1980s, the FDA published guidance documents that efficacy should be demonstrated by the following criteria:

  • Prolongation of life
  • Improved health-related quality of life
  • Or an established surrogate for one of these.

If the new therapy results in a statistically significant improvement, the new treatment is usually approved for clinical use.

Traditional endpoints

Traditional endpoints for trials have included:

  • Overall survival
  • Time to tumor progression
  • Overall response rate
  • Time to treatment failure
  • And patient-reported outcomes

Overall survival

Overall survival has been the gold standard for the demonstration of clinical benefits.

Subpart H allows for accelerated approval of drugs for serious and life-threatening diseases where the drug demonstrates an advantage over available therapy. This is based on a surrogate endpoint that likely predicts clinical benefit.

While randomized Phase III clinical trials have been the gold standard evidence for the approval of new drugs, problems associated with drug development have included:

  • Limited clinical benefit in large RCT’s
  • Prediction of a successful Phase III trial from Phase II data
  • Determination of toxicity
  • Design of studies with drug combinations
  • And the cost of the trial.

Adaptive designs

Ocana and colleagues suggest that adaptive designs in selected prescreened populations could reduce the limitations.

Statistical methods for the design and analysis of adaptive designs began in the 1990s.

However, many of the designs are not standard and relate only to the application being considered. The experience of sponsors and regulators in planning, conducting and interpreting results using these designs is limited and interaction with regulating authorities early is crucial.

In Europe, the European Medicines Agency offers developers of drugs and therapeutic devices scientific advice and protocol assistance.

In 2010, the FDA also published guidance on adaptive design clinical trials.

Evaluating adaptive clinical trials

Evaluators of adaptive clinical trial studies answer the following 6 questions:

  1. Is there a good rationale and have alternative designs been considered?
  2. Does the proposal fit well in the context of the development program and the data that will be available for the marketing authorization application?
  3. Can the proposal be implemented without important damage to trial integrity?
  4. Is the type I error rate controlled?
  5. Has the potential bias of treatment effect estimates been evaluated?
  6. Is the proposal practical and feasible?

These questions are also asked of other designs.

The European Organisation for Research and Treatment of Cancer recognize that these designs can be advantageous, but warn that they must prevent bias that could be uncontrollable.

Recommended techniques include:

  • Randomization
  • Blinding
  • Prospectively planned adaptations
  • And the upfront implementation of the process and firewalls needed to ensure restricted access to interim analysis results and blinding of staff involved in day-to-day trial proceedings

Source: Mahan, V.L. (2014) Clinical Trial Phases. International Journal of Clinical Medicine, 5, 1374-1383.

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