The starting point to do a trial well is to identify an important question to address. So much better, if this question emerges from a meta-analysis of the existing evidence as was the case with the ATLAS trial. The Early Breast Cancer Trialists Collaborative Group identified a number of small trials comparing 10 years treatment with tamoxifen with 5 years, but these early trials were too small to reliably assess the effects of longer treatment.
Patient and the public involvement in research, known as PPI, is very topical at the moment. Getting PPI right is neither simple or something that can be done without careful thought. There are logical points in the evolution of a research project that lend themselves to active involvement of patients and the public – these are:
- Formulation of the research question – is the question relevant to the population? Will the result be applicable to the population studied?
- Prioritisation of the research – is this the most important question to address in the study population? Will people want to take part?
- Research design – is the study feasible as planned? Can a sufficient number of people be recruited?
- Research conduct – how are people recruited? Are the study materials promoting participation? Can the design be simplified?
- Research outcome – how can the results be rapidly translated into practice? How does this study matter?
No single PPI exercise can check all of these boxes, but instead, patients and the public need to be engaged at the different stages of the research process. Deciding on the research question along with prioritising it is something that needs to happen early on, while matters to do with the conduct of the research can wait until the question is already formulated.
Ethics committees play an active and vital role in PPI, particularly in the aspects related to research design and conduct, but this is often overlooked as being separate from active patient and public involvement. This is not the case as ethics committees are formulated to promote discussion and dialogue between expert researchers and the members of ethics committees who represent patients and the public. These interactions are some of the most productive discussions and take place within the context of the ethical review of the project. Of particular note, is the process of ethical review of the participant information sheet and consent, which forms the central part of the request to participate and, as such, these discussions at the ethics committee are some of the most productive.
One aspect of ICH-GCP that appears to be lacking is proper recognition of the need for patient and public involvement in research. As has been pointed out previously, ICH-GCP still refers to research “subjects” rather than the correct term of “research participant.” Active involvement of patients and the public both early on and throughout the research is not a guarantee of success, but at the very least, it puts the research in a context that people should wish to participate if given the opportunity. Ethics committees play a vital role in this process and this should not be overlooked.
ICH-GCP states that it is an ethical standard for the design and conduct of research, but close inspection of the guideline leads to the conclusion that it is concerned with the process of ethics, specifically, the process of ethical review rather than the core principles of ethics. This is a pity because the principles that underpin research ethics are essentially straightforward and easy to grasp. I will try to outline them here.
Janet Darbyshire and colleagues from the MRC Clinical Trials Unit in London pioneered the conduct of a series of ground-breaking HIV treatment trials during the 1990s. One of these trials, The Delta trial randomised more than 3,200 patients to treatment with zidovudine (ZDV) alone or ZDV in combination with either didanosine (DDI) or zalcitabine (DDC). One of the questions the trial wanted to answer was whether combination treatment with DDI was superior to DDC.
The authors analysed this in two different ways. The first approach looked at the direct randomised comparison of patients randomised to either DDI or DDC. The second method identified those patients initially randomised to just ZDV and whose treatment was subsequently modified in an open-label fashion to include combination treatment with either DDI or DDC. Death was chosen as the study endpoint with the groups being similar in terms of selected risk factors for clinical progression. This means that the groups “looked” the same giving a false reassurance to be able to reliably investigate the effects of combination treatment across both the randomised and observational analysis.
The analysis clearly showed that in the randomised group ZDV plus DDI showed improved survival compared to ZDV plus DDC, but in the observation group the opposite effect was seen, namely combination treatment with DDC showed improved survival over DDI. Why might this be the case?
One explanation suggested by the authors is that in the observational group patients with a poorer prognosis are more likely to be prescribed DDI over DDC. This selection bias was not identified from the baseline analysis of selected risk factors for progression highlighting again the false reassurance that such results can confer. This highlights once again that only with a proper randomised comparison can selection bias resulting from known and unknown characteristics be reliably eliminated.
You can read the full paper here.
ICH are meeting in Montreal this week. Our letter to them clearly outlines the steps required to make it much easier to do randomised trials.
The starting point is to develop a new guideline on the key principles to do a randomised trial well which is developed by all key stakeholders in a transparent manner.
Download our letter here: