Use of clinical registries in phase 4 of DMT

At the time of authorisation, information on the safety of a medicinal product is relatively limited. This is due to the conditions in which in clinical trials are performed when compared with real life, including a smaller number of subjects, restricted population in terms of age (usually no children and older people), gender and ethnicity, restricted co-morbidity, co-medication, conditions of use, and relatively short duration of exposure and follow-up. Therefore, phase 4 research is very important.

The first step in phase 4 research is pharmacovigilance, i.e. the detection, assessment, understanding, and prevention of adverse events and other medicine-related problems. “The problem with pharmacovigilance is that it mainly relies on spontaneous identification”, Prof. Sandra Vukusic (Lyon University Hospital, France) mentioned. “Usually, pharmacovigilance research is very time-consuming. Furthermore, it is limited by reporting bias.” These challenges led to the introduction of risk-management plans by the EMA, a second step in phase 4 research. These plans are designed to identify, characterise, and prevent or minimise risks related to medicinal products, including the assessment of effectiveness. The next step comprises the secondary use of registry data. The rationale is to increase in the number of post-approval safety studies. “This is very time consuming, but, investigators have limited time.” Secondary use of registry data mostly means the application of data collected in routine clinical practice for all patients. This could fill the requirements of each individual risk-management plan on safety, efficacy, good use, and risk/benefit balance. Furthermore, phase 4 research is useful to mutualise human, financial, methodological, and technical means. The protocols of these studies can be designed collaboratively with health authorities, academics, and industry. An important aspect of phase 4 research is to reassure the quality of the data.

Alignment of research worlds

Compared to traditional post-marketing studies, the number of patients is much higher in drug registries (see Table). “Furthermore, in post-marketing studies, patients are selected, but for example children are excluded because age <18 years is an exclusion criteria in such studies. However, we need information about those patients”, Prof. Vukusic emphasised. “That is the case in registry studies, which deliver long-term data.” A shortcoming of registries is that there might be more patients lost to follow-up and missing data. The regulators in Europe are very interested in using registry data. This led to the publication of a discussion paper regarding the use of patient disease registries for regulatory purposes in November 2018 [1].

Table. Characteristics of clinical trials, traditional post-marketing studies, and drug registries

BigMSData registry

The BigMSData registry initiative started in 2011. “Between 2012 and 2016, we had a large pilot phase with 5 MS registries from Italy, Sweden, Denmark, France, and the international MSBase”, Prof. Vukusic added. In a feasibility phase, the differences and commonalities among the 5 registries were evaluated. Afterwards, it was decided to standardise the definitions and procedures, to ensure the possibility of merging data from different sources. Initially, 3 projects were proposed to validate the feasibility of pooling data:

• Impact of early treatment on long-term disability in relapsing-remitting MS patients [2];
• Treatment discontinuation in the BigMSData Network, a descriptive analysis, presented at ECTRIMS 2018 [3]; and
• Use of DMTs in the progressive phase (ongoing study by H. Butzkueven et al.).

“Because the quality of the data was good, it was possible to pool them”, Prof. Vukusic continued. “We can work together, so we can answer questions which we cannot answer using only our own data.” The next step was to create a core study protocol, aimed to assess and characterise the risk of certain safety events in MS patients who were exposed and unexposed to approved DMTs for the treatment of MS, by collecting serious adverse events in specific disease registries. An increasing number of DMTs are currently available, but, are yet to undergo post-approval safety studies. Several MS registries are currently mature, according to Prof. Vukusic. This includes the BigMSData network, which is open to other national registries in the future. There is a favourable context with an EMA initiative on disease registries and pharma agreeing to collaborate. “The direction is towards a more active, but less time-consuming participation of MS neurologists to the risk/benefit assessment of DMTs in the future.”

1. EMA/763513/2018. 5 November 2018.
2. Iaffaldano P, et al. ECTRIMS 2019, abstract 156.
3. Spelman T, et al. ECTRIMS 2018, abstract P1195.

Posted on 8 November, 201922 March, 2021