Analysis of the place of phase IV studies for drug risk assessment in vulnerable populations
During clinical development, the risk to the patient is monitored. However, when a health product is placed on the market, knowledge of its benefit-risk balance is only fragmentary. The post-marketing surveillance system, which makes it possible to update this balance, is based essentially on spontaneous reporting of adverse effects. What is the need for phase IV studies, in addition to clinical trial data and pharmacovigilance evaluation? The objective of our research is to study the complementary approach of phase IV studies and their interest in relation to phase III studies and pharmacovigilance data, by focusing on an example of a population that is little studied in clinical trials, the elderly, and old drugs, benzodiazepines and an effect occurring during long-term use, drug dependence. Our work shows that post-marketing studies are essential to know the risk and dependence profile of a drug, which evolves throughout its "life". Predicting possible situations of dependence, detour, etc. requires a good evaluation of the benefit-risk balance not only for medical use in the MA, but also in all off-label use situations, including non-medical use. These data are essential to understand the obstacles to the application of recommendations or regulations on proper use.
Applicability of randomised trials results in general medicine
Many clinical practice guidelines are based on randomised controlled trials performed in secondary or tertiary care settings and general practitioners questioned their relevance for primary care patients.
The first objective was to compare the intervention effect estimates between randomised controlled trials performed in primary care and randomised controlled trials performed in secondary or tertiary care settings by using a meta-epidemiological approach. There was no difference in intervention effect estimates between the two types of randomised trials with a ratio of odds ratio of 0.98 (95% confidence interval 0.88 to 1.08). Nevertheless, the main medical fields encountered in this study were not fully representative of the medical conditions encountered in primary care with many studies on psychiatry or addictology (38.2%) or pneumology (13.2%) and very few in endocrinology or cardiovascular diseases.
The second objective was to compare the characteristics of type 2 diabetes patients of general practices to those included in the randomised trials on which clinical practice guidelines are based. Primary care patients differed from patients included in randomised trials in many important aspects. They were older (mean±standard deviation 68.8 ±1.1 years vs 59.9 years [standardised difference 0.8]), had higher BMI (31.5 (6.93) kg/m2 vs 28.2kg/m2 [standardised difference 0.48]). They also had more hypoglycemic (80.7% vs 45.4% [standardised difference 0.89] than randomised trials patients, but less cardiovascular history (myocardial infarction: 7.6% vs 23.1% [standardised difference -1.14]).
Methodological and statistical aspects of within-person randomized trials evaluating a topical treatment in dermatology
To assess a topical treatment in dermatology, we may use a within-person (also called split-body) design. Randomization units are no longer patients but rather lesions or body sites. Experimental and control treatments are then applied simultaneously on the different lesions. This study design reduces the inter-observation variability, and therefore the number of patients to be included in the trial. However, this study design presents methodological constraints, notably a risk of intergroup contamination, named the “carry across effect”. The objective of this PhD thesis was to study the methodological and statistical aspects of within-person randomized clinical trials. The first part of this work presents a synthesis of the methodological aspects to be considered when using this design. This work was conducted by a group associating dermatologists and biostatisticians. In the second part, we performed a methodological review of within-person randomized trials published between 2017 and 2021. The methodological aspects identified in the first work were assessed and discussed in this review. The third work focused on the statistical analysis. Using a Monte-Carlo simulation study, we compared the statistical properties of several analysis methods (mixed models and generalized estimating equations). Finally, as an illustration, the last part presents a within-person randomized trial protocol for evaluating topical sirolimus in superficial lymphatic malformations. The within-person design has multiple methodological and statistical specificities that must be taken into account when planning and analyzing the study. Dermatologists and methodologists must also consider patient acceptability.
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Assessing the evolution of patient experience before and after kidney transplantation : exploring measurement invariance
End-Stage Renal Disease (ESRD) requires renal replacement therapies: dialysis or kidney transplantation.
Today, it is well-known that ESRD treatments impact the quality of life (QoL) of patients. Patients may perceive and interpret questionnaires differently over time: this phenomenon is called response shift (RS). Thus, observed changes in QoL may reflect not only a real change in QoL, but also a different perception of the questionnaires by patients over time (RS). The questionnaire’ perception and RS may also differ between patients who have experienced dialysis or not (preemptive).
The first objective of this dissertation was to evaluate and compare changes in QoL for preemptive and dialysis patients on the waiting list for kidney transplantation. The second objective was detecting and taking into account RS (before and after kidney transplantation) and measurement non-invariance between groups (dialysis and preemptive patients). To meet these objectives, several works have been realized. Thus, we have identified that QoL of dialyzed patients was generally lower than that of preemptive patients during the waiting list period.
Plus, RS has been detected, and we have observed that QoL level of patients adjusted on RS, tended to increase after kidney transplantation. Adaptation of specific therapeutic education programs for patients who have experienced dialysis or not would improve QoL of patients.