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Active-controlled, non-inferiority trials in oncology: arbitrary limits, infeasible sample sizes and uninformative
1AstraZeneca Pharmaceuticals, Global Clinical Information Science, Alderley Park, Macclesfield, UK. kevin.carroll2@astrazeneca.com
Abstract:
In oncology, it may not always be possible to evaluate the efficacy of new medicines in placebo-controlled trials. Furthermore, while some newer, biologically targeted anti-cancer treatments may be expected to deliver therapeutic benefit in terms of better tolerability or improved symptom control, they may not always be expected to provide increased efficacy relative to existing therapies. This naturally leads to the use of active-control, non-inferiority trials to evaluate such treatments. In recent evaluations of anti-cancer treatments, the non-inferiority margin has often been defined in terms of demonstrating that at least 50% of the active control effect has been retained by the new drug using methods such as those described by Rothmann et al., Statistics in Medicine 2003; 22:239-264 and Wang and Hung Controlled Clinical Trials 2003; 24:147-155. However, this approach can lead to prohibitively large clinical trials and results in a tendency to dichotomize trial outcome as either 'success' or 'failure' and thus oversimplifies interpretation. With relatively modest modification, these methods can be used to define a stepwise approach to design and analysis. In the first design step, the trial is sized to show indirectly that the new drug would have beaten placebo; in the second analysis step, the probability that the new drug is superior to placebo is assessed and, if sufficiently high in the third and final step, the relative efficacy of the new drug to control is assessed on a continuum of effect retention via an 'effect retention likelihood plot'. This stepwise approach is likely to provide a more complete assessment of relative efficacy so that the value of new treatments can be better judged.
Insights
New cancer drug trials can be improved with a stepwise approach. This method offers a more complete assessment of relative efficacy, aiding in better judging new treatment value.
Area of Science:
- Oncology
- Clinical Trial Design
- Biostatistics
Background:
- Placebo-controlled trials are not always feasible for evaluating oncology drugs.
- Active-control non-inferiority trials are used for new anti-cancer treatments, especially those with improved tolerability or symptom control but not necessarily superior efficacy.
- Current methods for defining non-inferiority margins can lead to large trials and oversimplified dichotomous outcomes (success/failure).
Purpose of the Study:
- To propose a modified stepwise approach for designing and analyzing active-control non-inferiority trials in oncology.
- To address the limitations of current non-inferiority margin definitions, such as trial size and outcome interpretation.
- To provide a more comprehensive assessment of a new drug's relative efficacy compared to existing therapies.
Main Methods:
- A stepwise design and analysis approach is introduced.
- Step 1: Trial sizing to indirectly demonstrate superiority over placebo.
- Step 2: Assess the probability of the new drug being superior to placebo.
- Step 3: Evaluate relative efficacy on a continuum using an 'effect retention likelihood plot' if superiority is likely.
Main Results:
- The proposed stepwise approach offers a more nuanced evaluation of anti-cancer treatments.
- It moves away from dichotomous 'success' or 'failure' outcomes towards a continuum of effect retention.
- This method can potentially lead to more efficient trial designs and interpretations.
Conclusions:
- The stepwise approach provides a more complete assessment of relative efficacy for new oncology treatments.
- It allows for a better judgment of the value of new therapies by considering both placebo and active control comparisons.
- This methodology enhances the interpretation of non-inferiority trials in oncology drug development.
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