Research question:

The objective of this investigation is to assess the benefit of newborn screening for 5q-linked spinal muscular atrophy (SMA). In the process, newborn screening for 5q-linked SMA in combination with earlier diagnosis and therapy is assessed in comparison with no 5q-linked SMA screening with regard to patient-relevant outcomes.

Conclusion:

No comparative interventional studies of the screening chain were available for the comparison of newborn screening for 5q-linked SMA versus no newborn screening. Therefore, interventional studies permitting the comparison of an earlier versus later treatment start as well as studies on diagnostic quality were used and combined by means of the linked evidence approach.

For the comparison of an early versus late symptomatic treatment start, 1 small randomized controlled study with a short follow-up period can be used; it examined drug therapy in comparison with a sham procedure in children with infantile 5q-linked SMA. For the combined outcome of time to death or permanent ventilation as well as for the outcome of motor milestone achievement, subgroup analyses revealed effect differences between children with an early symptomatic treatment start (disease duration ≤ 12 weeks) and children with a later treatment start (disease duration > 12 weeks). For both outcomes, children benefit more from an early symptomatic treatment start than from a late symptomatic treatment start. The outcomes of serious adverse events, severe adverse events, and treatment discontinuation due to adverse events each showed no effect differences between subgroups. For other outcomes, no usable data were available.

For the comparison of a presymptomatic versus an early symptomatic treatment start, 1 small retrospective comparative study, which was made available by the manufacturer upon request, was included. Data were available on children with diagnosed 5q-linked SMA and 2 survival motor neuron (SMN)2 copies (i.e. prognosis or confirmation of infantile SMA). For the outcome of motor milestone achievement, large effects were found in favour of a presymptomatic treatment start over early symptomatic treatment start (disease duration ≤ 12 weeks); these effects were not explicable solely by bias (dramatic effect). For the outcomes of serious adverse events and severe adverse events, statistically significant differences were found in favour of a presymptomatic treatment start. These observed differences were assessed as small enough to be explicable solely by the effect of confounders. For each of the outcomes of overall survival, permanent ventilation, treatment discontinuation due to AEs, and back pain, no statistically significant differences were found. The criteria of a dramatic effect were not met. No data were requested on other outcomes.

It was not possible to include any comparative interventional studies on patients with a later disease onset than in the infantile form.

For the assessment of diagnostic quality, it was possible to include 4 studies, but these studies verified only positive test results (verification-of-only-positive-testers design). The results of these studies suggest that the examined test methods are suitable for newborn screening for 5q-linked SMA. It remains unclear how many affected children were missed by the testing.

In summary, there is an indication of benefit of newborn screening for 5q-linked SMA when compared with no screening. This result is based, first, on data on the presymptomatic, early symptomatic, and late symptomatic drug treatment of children with diagnosed 5q-linked SMA and a prognosis or confirmation of the infantile form. The included data show an association between timing and effect according to which an earlier treatment start is associated with better treatment results. Second, the derivation of an indication of benefit of newborn screening is based on the suitability of diagnostic test methods and the opportunity to achieve an earlier diagnosis (and hence treatment) by means of newborn screening. The available data do not permit drawing any conclusions as to whether children identified by the screening to have late-onset SMA (i.e. symptom onset not until years later) would benefit from a presymptomatic treatment start. Currently, it is therefore especially unclear how to handle newborns who test positive in the screening and are expected to have late-onset disease (≥ 4 SMN2 copies). If newborn screening is introduced, it will be essential to consider how to appropriately handle these children and their families – including the option of letting them decide for themselves whether or not they wish to know about the presence of mild courses of SMA forms.

Publisher

Institute for Quality and Efficiency in Health Care

Topic

Newborn screening for 5q-linked spinal muscular atrophy

Commissioning agency

Federal Joint Committee

Commission awarded on

13 December 2018

Internal Commission No.

S18-02

Address of publisher

This report was prepared in collaboration with external experts.

The responsibility for the contents of the report lies solely with IQWiG.

According to §139b (3) No. 2 of Social Code Book (SGB) V, Statutory Health Insurance, external experts who are involved in the Institute’s research commissions must disclose “all connections to interest groups and contract organizations, particularly in the pharmaceutical and medical devices industries, including details on the type and amount of any remuneration received”. The Institute received the completed Form for disclosure of potential conflicts of interest from each external expert. The information provided was reviewed by a Committee of the Institute specifically established to assess conflicts of interests. The information on conflicts of interest provided by the external experts and external reviewers is presented in Chapter A8 the full report. No conflicts of interest were detected that could endanger professional independence with regard to the work on the present commission.

External experts

• Tim Mathes, Institute for Research in Operative Medicine, Witten/Herdecke, Germany
• Barbara Prediger, Institute for Research in Operative Medicine, Witten/Herdecke, Germany
• Benedikt Schoser, Friedrich Baur Institute, Neurological Clinic, Ludwig Maximilians University Munich, Germany

IQWiG thanks the external experts for their collaboration in the project.

IQWiG employees

• Lina Rodenhäuser
• Andrea Steinzen
• Inga Overesch
• Anne Rummer
• Lisa Schell
• Wiebke Sieben
• Sibylle Sturtz
• Vera Weingärtner