Lack of direct comparisons prevents assessment of upadacitinib's benefit in Crohn's disease

Like several immunosuppressive biologics, the JAK inhibitor upadacitinib is also approved for the treatment of Crohn's disease. Commissioned by the Federal Joint Committee (G-BA), the Institute for Quality and Efficiency in Health Care (IQWiG) has now investigated in an early benefit assessment whether the drug offers an added benefit versus the appropriate comparator therapy to patients with moderate to severe active Crohn's disease who have had an inadequate response, lost response or are intolerant to conventional therapy or a biologic agent.

Therefore, an added benefit is not proven due to a lack of suitable study data. The studies presented by the company in its dossier only compared different concentrations of upadacitinib and placebo.

Selection of biologics as appropriate comparator therapy

Crohn's disease is a chronic inflammatory bowel disease in which inflammation can occur throughout the digestive tract. Among others, immunosuppressive biologics such as the TNF-α antagonists adalimumab or infliximab, the integrin inhibitor vedolizumab or the interleukin inhibitor ustekinumab are used to suppress disease flares. The first biologic approved for the treatment of Crohn's disease was infliximab in 1999.

In its commission for assessment to IQWiG, the G-BA distinguished between two situations: inadequate or absent response or intolerance to a conventional therapy on the one hand and to a biologic on the other. In both research questions, upadacitinib was to be compared with a TNF-α antagonist (adalimumab or infliximab) or an integrin inhibitor (vedolizumab) or an interleukin inhibitor (ustekinumab). Affected patients who had already received a biologic without success were to be treated with another biologic from this spectrum. Pure dosage changes were not an option; the G-BA assumed that this option had already been exhausted for those affected.

Although the manufacturer confirms the usefulness of these comparator therapies, it does not present any randomized controlled trials suitable for deriving an added benefit. In all three approval studies mentioned by it, the drug was only compared with placebo and with other doses of upadacitinib. The biologics that the G-BA cited as appropriate comparator therapies were also not allowed to be used as concomitant treatments.

This leads to the following conclusion: An added benefit of upadacitinib in comparison with the appropriate comparator therapy is not proven for patients with moderate to severe active Crohn's disease who have had an inadequate response, lost response or are intolerant to conventional therapy or a biologic agent.

Where are the direct comparisons?

"Biologics have been approved and used in the therapeutic indication of Crohn's disease for over twenty years – and yet we are still presented with studies in which new immunosuppressive substances are only compared with placebo or with themselves in different doses," says Daniela Preukschat from IQWiG's Drug Assessment Department, wondering. The situation is similar for other therapeutic indications, for example ulcerative colitis, also a chronic inflammatory bowel disease. A study on Crohn's disease, which was used in the benefit assessment procedure for risankizumab, shows that there is another way: the benefit assessment compared risakizumab with ustekinumab.

Manufacturers can certainly start studies early before market entry to provide meaningful evidence for care. This shows: You just have to want it."

Daniela Preukschat from IQWiG's Drug Assessment Department

G‑BA decides on the extent of added benefit

The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.

You can find an overview of the results of IQWiG's benefit assessment in an English extract. In addition, the website informedhealth.org published by IQWiG provides easily understandable information on this benefit assessment.