Newborn screening for spinal muscular atrophy assessed by IQWiG in Germany

On behalf of the Federal Joint Committee (G-BA), the Institute for Quality and Efficiency in Health Care (IQWiG) investigated whether a test of newborns for spinal muscular atrophy (SMA) in Germany would make sense. The affected children benefit from early diagnosis, as this enables an earlier start of therapy.

SMA is a group of inherited neuromuscular disorders that result in the loss of motor neurons and progressive muscle wasting. The condition affects about 1 in 10,000 people at birth. SMA is a leading genetic cause of death in infants - in the case of infantile-onset SMA, the ultimately progressing symptoms lead to permanent ventilation and death.

This SMA has not yet been examined in the context of advanced newborn screening. In this screening, which is carried out in Germany in accordance with the Children’s Guideline of the G-BA, venous or heel blood is obtained in the 36th to 72nd hour of life, dripped on filter paper cards and examined for the presence of various diseases.

A systematic literature search was carried out in the databases MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. In parallel, a search for relevant systematic reviews in the databases MEDLINE, Embase, Cochrane Database of Systematic Reviews, and HTA Database was carried out.

As a result, 1 study (14 documents) with data comparing an early versus a late symptomatic start of therapy was identified. Furthermore, the manufacturer provided data for the comparison of a presymptomatic with an early symptomatic start of treatment, which was included in the sense of 1 retrospective comparative study (1 document). No other planned or ongoing comparative intervention studies regarding the start of therapy were identified. Also, four completed studies (seven documents) and three ongoing studies on the diagnostic quality were identified.

Results - early symptomatic versus late symptomatic therapy start:

• According to ENDEAR study, a statistically significant difference between the subgroups of early and the late symptomatic start of therapy (disease duration ≤12 />12 weeks) in children with infantile-onset SMA (p = 0.008) was identified. The same direction of effect was shown for the individual components, whereby there was also a statistically significant difference for the individual component time to permanent ventilation (p = 0.040)
• In line with the Hammersmith Infant Neuromuscular Examination Section 2 (HINE-2) results, there was a statistically significant difference between the subgroups of early versus late symptomatic treatment initiation (p = 0.003). Within the subgroups, there was a statistically significant difference in favor of Nusinersen treatment (early symptomatic therapy start: RD: 0.71; 95% CI: [0.55; 0.86]; p <0.001; late symptomatic therapy start: RD: 0.37 ; 95% CI: [0.23; 0.51]; p <0.00).

Results - presymptomatic versus early symptomatic therapy start:

• In line with the Biogen 2019 study, the changes in the overall HINE-2 score from the time the study started to the age of 1 year differ very clearly between the groups in favor of the presymptomatic compared to the early symptomatic start of therapy (Hedges’ g: 3.62; 95% CI: [2.38; 4.86]).

Results – diagnostic quality:

• According to Chien 2017 study, a 2-step procedure was used to evaluate the blood samples. In the first step, 15 newborns were tested positive using reverse transcription polymerase chain reaction (RT-PCR). In a second step, the same sample material from these 15 newborns was examined with a downstream droplet digital PCR (ddPCR). Using this two-step procedure, no false-positive results were obtained, i.e., both PPV and specificity were 100% (PPV 100; 95% CI: [64.6; 100])
• In the ongoing study Czibere / Vill 2019, in which the blood samples were evaluated using quantitative PCR (qPCR), no false-positive results were reported for a data cut after one and a half years, i.e., both PPV and specificity are 100% (PPV 100; 95% CI: [88.6, 100]). A total of 30 newborns with 5q-associated SMA have been identified in this study so far
• In the Kraszewski 2018 study, in which the evaluation was also carried out using qPCR, no false-positive results were reported. This means that in this study too, both PPV and specificity were 100% (PPV 100; 95% CI: [20.7; 100] with one positive newborn).

It was summarized that comparative intervention studies of the screening chain could not be identified. For the combined endpoint time to death or permanent ventilation and the endpoint reaching motor milestones, children benefit more from an early symptomatic than from a late symptomatic start of therapy.

Data were available on the comparison of a pre- versus an early-symptomatic start of therapy. There is a dramatic difference for the endpoint of reaching motor milestones and, thus, a hint for a higher benefit of a presymptomatic start of treatment compared to an early symptomatic start of therapy.

The results of the diagnostic quality studies indicate that the test methods examined are suitable for screening in newborns for 5q-associated SMA. Data on the number of false-negative results are not available.

Overall, based on the combination of the available results at the start of therapy and the diagnostic quality using a linked evidence approach, a hint for the benefit of newborn screening for 5q-associated SMA is identified in comparison to no newborn screening.

The preliminary report was published by IQWiG in October 2019 and put up for discussion. After completing the discussion procedure, the project team revised the preliminary report and sent it to the client, the G-BA, as the final report in February 2019. The written comments submitted were published in a separate document at the same time as the final report.

The full details in German can be found here.

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