Despite their effectiveness in the evaluation of new pharmacological compounds, controlled clinical trials are sometimes inadequate. Using data from the literature as well as from the author's own experience with clinical trials, Human Experimentation: Methodologic Issues Fundamental to Clinical Trials addresses such inadequacies and tries to provide solutions.
This work is the first to thoroughly examine these unsolved inadequacies and problems with the design and the execution of clinical trials and, more importantly, to provide solutions for these problems. It is important for anyone who is involved in clinical research: clinicians, pharmacists, biochemists, statisticians, nurses, sponsors, etc. The author of more than peer-reviewed scientific articles, Dr.
Piantadosi has published extensively on research results, clinical applications, and trial methodology. While his papers have contributed to many areas of oncology, he has also collaborated on diverse studies outside oncology including lung disease and degenerative neurological disease. Piantadosi is one of the world's leading experts in the design and analysis of clinical trials for cancer research.
He has taught clinical trial methods extensively in formal courses and short venues. Permissions Request permission to reuse content from this site. Wiley Series in Probability and Statistics. Undetected location. NO YES. The National Institute of Health in the USA highlighted that few publications on palliative care research reflected the growing needs of patients [ 33 ].
Even in the context of symptomatic control research, important gaps in clinical evidence should be addressed. For example nonpain symptoms, such as breathlessness or delirium, are still poorly understood and symptom burden continues to be the main complaint of patients and cause of dropout from studies despite relief of distressing symptoms being considered one of the guiding principles for palliative care practitioners [ 10 , 34 ]. The definition of palliative care points towards a population with life-limiting disease and, when cure is not possible, what is frequently understood as the care of patients in their last weeks or days of life [ 10 , 35 ].
However, some diseases, especially chronic diseases, severely affect the quality of life of patients and family members for many years, this led to considering palliative care earlier, and including in more recent definitions the initiation of palliative care at the time of diagnosis and provided concordantly with all other disease-directed or curative treatments [ 10 ].
Of the identified citations, only This is in line with previous methodological reviews, Hui et al. In , Aoun and Nekolaichuk [ 9 ] reported that Cochrane reviews in palliative care failed to provide good evidence because of the few numbers and poor internal and external validity of primary studies. Although these types of studies are a minority in palliative care research, our results show that the number CCTs has increased in recent years.
The samples of the included studies vary between 9 and participants, with a median of It is not uncommon to find statements suggesting that it is unethical to involve people with palliative care needs in research because of their increased vulnerability [ 27 ]. Aoun and coworkers [ 9 ], in a review about the challenges of evidence-based medicine EBM in palliative care research demonstrated precisely the opposite: the participation in experimental protocols was not perceived as an additional stress, but rather like a personal gain in a selfless perspective related with a moderate-to-high benefit.
To caregivers, this collaboration is seen as an added value for patients, for themselves, and for future families that need palliative care assistance. Recently, the result of a workshop and consensus exercise MORECare study , about best practice on ethical concerns in PC research [ 33 ], affirmed that it is ethically desirable for patients and their families with palliative care needs to be offered the opportunity to be involved in research and reminded of the existence of relevant international recommendations to overcome some of the ethical challenges faced.
Abernethy et al. A review by Hui et al. It is unavoidable to have some missing data, but ignoring it is not acceptable, since it represents a significant risk to the power, precision and generalizability of trials results. Looking at our pooled results, there was a higher percentage of dropouts in intervention arm.
Hussain et al. Furthermore, Bell et al.
The authors suggested the use of mixed models methods as a strategy to estimate unbiased treatment effects, under assumptions regarding the misingness mechanism s. Of the included clinical trials, only This is a major problem in clinical research because, as mentioned above, it can be misleading either by missing realistic moderate treatment effects that would be clinically important, or by overestimating the size of a treatment effect and finding it statistically significant purely due to chance [ 38 ].
Besides the large diversity of study outcomes, our results demonstrate the absence in a significant percentage of studies Because of the great heterogeneity in population and type of interventions, there is still a lack of consensus in palliative care field about the best outcome measures and clinically meaningful differences for each outcome.
In this review only 3.
The choice of assessment tools is very important in study protocols and one of the challenges of reaching high quality research. Although several instruments can be used to assess outcomes, not all were developed and validated for use in a palliative care population and so not the most appropriate [ 39 ]. Best supportive care BSC interventions were defined by Jassem et al. However, this method has been criticised for poor reporting and for lack of standardisation among trial participants.
To overcome these threats, Nipp et al. In two articles [ 44 , 45 ] with arguments for and against placebo-controlled trials in palliative care were published. Hardy et al. A key finding of this systematic review was the low overall reporting quality of CTs in palliative care and the amount of missing data in trial reporting. Although the number of published studies has increased significantly in the last years, we found no relevant improvement in the overall methodological quality of studies. A review of evidence-based practice in palliative care from [ 5 ] supports our findings and attributes the poor quality of trials to the barriers that were already mentioned in this review, such as difficulties in recruitment, in reaching samples with a significant power, and in defining outcomes.
In another study from the authors state that recent reviews in the field continue to report a lack of strong evidence for important topics, due in part to the methodological weaknesses in the existing studies [ 46 ]. Allocation concealment and blinding were the aspects poorly reported.
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Lai [ 47 ], in a systematic review of primary treatment in brain tumours, suggested that allocation concealment, blinding, type of analyses and details of randomisation were the poorly reported aspects because of the researcher difficulty in reporting this type data and due to the lack of awareness of the importance of these features. Regarding blinding, in many interventions this method is difficult to apply. However, it is important to use it to minimise bias, especially when the outcome of interest is subjective [ 48 ]. The assessment of this item was based on comparability of trial arms and sample size calculations, but most of all with a global evaluation of methodological flaws and amount of missing information in each trial Additional file 4.
Studies with major gaps in other key methodological characteristics commonly also did not fulfil our criteria for a low risk of other bias. Quality of a clinical trial is a multidimensional concept that includes study design, conduction, type of analysis, clinical relevance and quality of reporting [ 49 ].
In this review we evaluated the quality of reporting, and based on this indirectly inferred studies quality. The focus on the assessment of trial reporting is based on the evidence that studies of lower methodological quality tend to report larger treatment effects than high quality studies [ 50 — 52 ]. It cannot be excluded that obtaining additional information from study protocols or directly from trial investigator could ensure a more accurate assessment of studies quality [ 9 , 53 ].
Chen et al. Although the current study had included a pre-specified search strategy and two independent investigators performed the selection, we were restricted to one database MEDLINE , which can not ensure we have identified all studies that meet the eligibility criteria. As mentioned above, there is a large variability in palliative care terminology. As a result, the number of retrieved citations was high, with an elevated percentage of manuscripts that did not meet inclusion criteria for clinical trials.
Of the identified citations, met the inclusion criteria and were analysed. Compared with previous reviews, our search strategy generated the largest list of clinical trials concerning therapeutic interventions in palliative care appraised and we believe that our results are representative of interventional studies in PC. With palliative care research becoming increasingly necessary it is not enough to conduct more studies, it is also necessary to improve the quality of evidence. Palliative care research is trying to deal with the large heterogeneity, the ethical and methodological issues resulting from the expansion of its scope of intervention, while at the same time it still seems too tied to the concept of terminal care of oncological patients, with a level of quality of reporting that has not evolved.
To our knowledge, this is the most comprehensive attempt to review clinical trials in palliative care literature. According to our results, it seems that the first step in generating not just valid, but also generalisable knowledge, is to clearly define palliative care populations, types of intervention and time to referral, establishing a common lexicon for clinicians and researchers. This will allow consensus to be achieved on the best outcomes and clinically meaningful differences, and will facilitate the choice of study design as well as promoting strategies to bypass the major barriers in palliative care research.
How are palliative care cancer populations characterized in randomized controlled trials? A literature review.
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