The Federal Joint Committee (G-BA), the highest decision-making body in the German health care system, commissioned the Institute for Quality and Efficiency in Health Care (IQWiG) to assess a total of 10 drugs for the treatment of multiple sclerosis (MS): The immunomodulators cladribine, dimethyl fumarate, ozanimod, ponesimod, teriflunomide, and fingolimod, as well as the monoclonal antibodies alemtuzumab, natalizumab, ocrelizumab and ofatumumab, are designed to have a beneficial effect on the immune system of patients with relapsing-remitting multiple sclerosis (RRMS), the most common form of MS.
The course of this chronic disease can vary greatly, so that different treatment strategies are needed at different stages. IQWiG therefore analysed the advantages and disadvantages of the above drugs in 4 different treatment strategies for adults with highly active RRMS despite previous treatment. IQWiG used face-to-face interviews to find out what is most important to patients: How the disease affects their lives and daily routines, how they cope with it, what the goals of treatment are, and what their experiences of treatment have been.
Therapeutic uncertainty due to evidence gaps after drug approval
The final results of the benefit assessment are incomplete. Even after the commenting procedure and the oral debate, although study data on escalation therapy are available for 7 of the 10 drugs, direct comparative data are scarce. Results from such head-to-head comparisons are available for 3 drugs, showing that ofatumumab and ponesimod (each compared to teriflunomide) provide greater benefit to patients. For 2 drugs, the manufacturers did not submit any data for the benefit assessment.
In the only study that provides data comparing escalation with continuation of an existing therapy, alemtuzumab as an escalation therapy is superior to interferon-beta 1a as a basic therapy. Therefore, it is not possible to draw conclusions about the benefit of the 10 drugs in relation to each other.
De-escalation, i.e. reducing the dose or the number of drugs, could be useful if the disease is inactive or if a drug is associated with intolerable side effects. However, relevant studies for such treatment strategies are lacking, even though they are important treatment approaches for many patients.
Finally closing gaps in health care – for good patient care
IQWiG’s assessment is the first analysis to compare drugs approved until 2021 within escalation therapy for pre-treated patients with highly active RRMS. In addition to the advantages shown by 3 out of 10 drugs, the other key finding is the existence of huge research gaps.
IQWiG’s Director Thomas Kaiser states: "Our benefit assessment is only based on comparisons of escalation therapy. Data for most other comparisons and treatment strategies are lacking. For 2 drugs, the manufacturers did not provide us with the necessary documents even after the commenting procedure and oral debate – a legal obligation in this regard would be desirable. In addition, in some cases, data on relevant outcomes were not collected in individual studies. The problem is that there are only a few direct comparative studies and indirect comparisons based on the existing studies are only possible to a limited extent. For 2 health care-relevant questions there were no studies at all."
Daniela Preukschat, Head of the Chronic Diseases Division in IQWiG's Drug Assessment Department notes: "The report shows that there is a huge lack of health care-relevant data. It is essential that patient-relevant outcomes, such as visual impairment, fatigue and health-related quality of life, are included in the study design. The importance of these outcomes, but especially evidence on targeted de-escalation and long-term follow-up of affected patients, was also highlighted during the oral debate on the preliminary report."
According to Thomas Kaiser, these research gaps could be effectively filled by reliable comparative studies, in particular registry-based randomized controlled trials (RRCTs). He further explains: "The structural barriers to closing evidence gaps, such as the funding of the often-expensive study drugs or organizational hurdles, can be removed. The current discussions on the Registry Act already suggest effective starting points for this. With the MS Registry, we have good structural conditions in the field of MS to conduct an RRCT on de-escalation strategies. The oral debate on our report shows that with a joint effort by self-help groups, scientific societies and industry, this should be possible."
Procedure of report production
On 16 July 2020, the G-BA commissioned IQWiG to assess the benefit of alemtuzumab, cladribine, dimethyl fumarate, fingolimod, natalizumab, ocrelizumab, ofatumumab, ozanimod, ponesimod and teriflunomide for the treatment of adults with highly active RRMS. IQWiG published the preliminary results, the preliminary report, in April 2023 and invited comments. At the end of the commenting procedure, the report was revised and sent to the G-BA as a final report in September 2023, which was published in October 2023. The English translation was published in February 2024. The written comments submitted on the preliminary report were published in separate documents at the same time as the final report. The Institute involved external experts in the project.