Linaclotide in irritable bowel syndrome: added benefit not proven

Linaclotide (trade name: Constella) has been approved in Germany since November 2012 for the treatment of adults with moderate to severe irritable bowel syndrome (IBS) with constipation. In an early benefit assessment pursuant to the Act on the Reform of the Market for Medicinal Products (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG) examined whether this new drug offers an added benefit over the current standard therapy.

An added benefit is not proven because the dossier did not contain any relevant studies: The appropriate comparator therapy was not implemented adequately in any of the three studies cited by the drug manufacturer. Moreover, the treatment phases in two of these studies were too short for a drug that is approved for maintenance treatment.

Diet was not changed in the studies

In IBS, the intestinal muscles move the food mass too slowly so that too much water is absorbed from it. This can lead to constipation, abdominal pain, bloating and cramping. Linaclotide aims to improve digestion and thus relieve the symptoms. Dietary changes under medical consultation and symptomatic treatment are commonly recommended for IBS. This was also how the Federal Joint Committee (G-BA) defined the appropriate comparator therapy.

Although the manufacturer explicitly accepted this comparator therapy, the study documents presented did not provide any information about whether dietary advice and possibly resulting dietary changes had taken place – if not in the studies themselves, then at least shortly before enrolment. In two of the three studies, the patients were explicitly instructed not to change their diet. In the third study, there was no information provided on this topic at all.

Uncertainties in the treatment of symptoms

Moreover, it remained unclear whether the symptomatic treatment, which was also supposed to be part of the comparator therapy, was implemented adequately. The patients in all the studies were not allowed to use a considerable number of treatments used for IBS symptoms, including laxatives and enemas. Only an emergency medication for constipation was permitted. No medication was explicitly permitted for abdominal bloating, cramping and pain, not even in emergencies. The options for individual treatment according to the patients' needs were therefore very limited.

Study duration too short for maintenance treatment

Another problem was that two of the three studies only lasted 12 weeks and were therefore too short to assess a drug that is meant and approved for long-term continuous treatment. IBS typically has a fluctuating course, so that treatment and observation should last at least 24 weeks.

Hence, none of the three studies presented was suitable to investigate the added benefit of linaclotide versus the appropriate comparator therapy specified by the G BA.

G-BA decides on the extent of added benefit

The dossier assessment is part of the overall procedure for early benefit assessments supervised by the G-BA. After publication of the manufacturer’s dossier and IQWiG’s assessment, the G-BA conducts a commenting procedure, which may provide further information and result in a change to the benefit assessment. The G BA then decides on the extent of the added benefit, thus completing the early benefit assessment.

An overview of the results of IQWiG's benefit assessment is given by a German-language executive summary. In addition, the website gesundheitsinformation.de, published by IQWiG, provides easily understandable and brief German-language information on linaclotide.

The G-BA website contains both general English-language information on benefit assessment pursuant to §35a Social Code Book (SGB) V and specific German-language information on the assessment of linaclotide.