3 Clinical evidence

3 Clinical evidence

Summary of clinical evidence

3.1 Full details of all clinical outcomes considered by the Committee are available in the assessment report overview.

3.2 The key clinical outcomes for the MAGEC system presented in the decision problem were:

  • the total number of surgical procedures and anaesthetics

  • the total number of outpatient attendances and procedures

  • recovery time

  • total length of stay

  • rate of distraction procedure success

  • infection rates and other surgical complication rates

  • total number of imaging procedures

  • quality of life

  • device failure

  • device and radiation exposure-related adverse events.

3.3 The sponsor addressed 5 of the outcome measures defined in the decision problem, and added additional outcomes including Cobb angle (a measure of spinal curvature based on a spinal radiograph), thoracic and total spine height. Outcomes relating to pulmonary function were also reported. The sponsor stated that these outcomes were reported in clinical studies, whereas several outcomes in the scope, such as quality of life, recovery time and total length of stay were not and could, therefore, not be addressed.

3.4 The sponsor identified 4 published and 6 unpublished studies relevant to the MAGEC system. The sponsor excluded 2 of the unpublished studies because they were records of ongoing clinical trials and had not reported any findings. The remaining 8 papers were included in the sponsor's summary of clinical evidence (Akbarnia et al. 2012, 2013a, 2013b; Cheung et al. 2012; Dannawi et al. 2013; Ellipse Technologies Inc. 2013; Richards and Nnadi 2013; Yoon et al. 2013). The study by Akbarnia et al. (2012) was excluded from further consideration because it was an animal study. The unpublished study by Richards and Nnadi (2013) was excluded because it was a cost analysis, but this report was included as economic evidence elsewhere in the submission. The studies by Akbarnia et al. (2013b) and Yoon et al. (2013) were excluded from the sponsor's evidence synthesis because they described patients already included in the studies by Ellipse (2013) and Dannawi et al. (2013) respectively. In summary, 6 studies formed the basis of the sponsor's clinical evidence presentation, of which 4 were included in the evidence synthesis. The External Assessment Centre considered that the studies presented by the sponsor were in keeping with the scope and were appropriate for inclusion.

3.5 Akbarnia et al. (2013a) reported preliminary findings from a prospective, observational multicentre study involving 14 children with early-onset scoliosis who received the MAGEC system rods. The mean age of the participating children was 8 years 10 months, with a range of 3–12 years. Single-rod surgery was carried out in 5 children and dual-rod surgery in 9 children. All children were given a brace for 3–6 months after surgery. The mean follow-up time was 10 months and the mean number of distractions per child was 4.9. The mean pre-operative Cobb angle was 60°. Post-operatively, the mean Cobb angle was 34° initially and 31° at the latest follow-up. Mean pre-operative thoracic spine height was 178 mm, increasing to 198 mm after surgery and 208 mm at the latest follow-up. Mean pre-operative total spine height increased from 292 mm pre-operatively to 322 mm post-operatively and 338 mm at final follow-up. The changes in total spine height were all reported to be statistically significant (p<0.05). No significant differences in the Cobb angle correction were found between children receiving single or dual rods. Complications included superficial infection in 1 child with a single rod, a prominent implant in 1 child with dual rods, and partial loss of initial spine height in 3 children with single rods immediately after surgery. Partial loss of distraction (a reduction in rod length) was observed after 11 out of 68 distractions but was subsequently regained.

3.6 Cheung et al. (2012) reported a prospective case series, reviewing outcomes for 2 children with scoliosis receiving MAGEC system rods, followed up for 24 months. A single rod was used for a 5-year-old child and dual rods for a 12-year-old child. Both children wore a brace for 3 months post-operatively. Distractions were carried out monthly in an outpatient setting, with an average lengthening of 1.5–2 mm. X-rays were used to measure the Cobb angle, spine height and amount of distraction. Pain was assessed using a visual analogue scale to produce a pain score and the children also completed a quality-of-life questionnaire for scoliosis (SRS-30). The child with a single rod had a change in Cobb angle from 74° pre-operatively to 19° immediately post-surgery and 26° after 24 months. In the child with dual rods, the Cobb angle changed from 60° pre-operatively to 31° after surgery and remained at 31° after 24 months. The authors reported the mean change in length of the instrumented segment of the spine after each distraction to be 1.9 mm±0.4 mm. Mean thoracic spine height increased from 199 mm at baseline to 203 mm post-operatively and subsequently to 229 mm after 24 months. Mean total spine height increased from 314 mm at baseline to 331 mm after surgery and 360 mm after 24 months. The authors reported that the mean monthly increases in spine height were greater than those predicted by standard growth charts. The pain score was 0 (no pain) pre-operatively and at each stage of follow-up. Superficial infection occurred in 1 child. Loss of distraction occurred after 1 of 43 procedures. This related to an excess bending moment in the rod causing slippage in the magnetic section, which led the sponsor to make an improvement in the rod's design (described in section 2.3).

3.7 Dannawi et al. (2013) reported a prospective case series involving 34 children with early-onset scoliosis receiving the MAGEC system rods in a UK hospital. Children were included if they had progression of curvature greater than 10° over 6 months and a Cobb angle greater than 40°. The mean age of the children was 8 years, ranging from 5 to 12 years. Mean follow-up time was 15 months, with a minimum of 12 months. Single rods were used for 12 children and dual rods for 22 children. Each child received at least 3 distractions and the mean number of distractions per child was 4.8 (range 3–6). Surgery with conventional growth rods had already been carried out in 2 children before conversion to the MAGEC system rods at their parents' request (to potentially reduce the number of surgical procedures for their children). These children had Cobb angles of 75° and 80° at the time of conversion. Distractions were carried out approximately every 3 months (mean 87 days) in an outpatient setting with the aim of achieving 4.5 mm growth following each distraction. Cobb angle and total spine height were measured pre- and post-operatively. The mean pre-operative Cobb angle was 69°. This decreased to a mean of 47° post-operatively and to 41° at final reported follow-up. The mean pre-operative total spine height was 304 mm: this increased to 335 mm immediately after surgery and to 348 mm at final review. The differences between Cobb angle measurements pre- and post-operatively and after follow-up in the single (n=12) and dual rod (n=22) groups were found to be statistically significant within each group (p<0.001). Similarly, the differences in the mean total spine height pre- and post-operatively and after follow-up in each group were statistically significant (p<0.001). Superficial infection occurred in 2 children, and there were 2 rod breakages needing revision. Loss of distraction occurred in 2 children, which was later rectified. This contributed to the subsequent revision of the rod design, as did the study by Cheung et al. (2012).

3.8 The unpublished study by Ellipse (2013) was a retrospective review including 54 children with early-onset spinal deformity associated with thoracic insufficiency (inability of the thorax to support normal respiration or lung growth) receiving MAGEC system rods. Children were included from 15 centres in 8 countries. Of these, 30 children had MAGEC rods inserted as their first (de novo) surgery and 24 had had previous spinal surgery to insert conventional growth rods. The sponsor's submission included a study report describing outcomes for 14 of these children. The sponsor supplied further data on all 54 children but the External Assessment Centre only included data on the 30 de novo patients from the original submission because it considered that revision surgery outcomes may not be directly comparable with those for initial surgery. The mean age of the 30 included children was 7 years, ranging from 2 to 10 years. Out of the 30 children having de novo surgery, 9 received a single rod and 21 received dual rods. Mean follow-up time for the children having de novo surgery was 21 months. At baseline the Cobb angle was measured in 28 children and total spine height was measured in 27 children. Thoracic spine height and space available for lungs (SAL) were also measured and each measurement was repeated post-operatively and at follow-up. The mean Cobb angle changed from 64° at baseline to 35° post-operatively and then to 43° at final follow-up. The mean total spine height was 264 mm pre-operatively, increasing to 308 mm post-operatively and 312 mm at final follow-up. The mean thoracic spine height increased from 164 mm pre-operatively to 192 mm post-operatively and 194 mm at final follow-up. These differences were found to be statistically significant (p<0.001). The change in SAL was reported for 5 children who had a baseline SAL of less than or equal to 90%. For these 5 children, mean SAL increased by 27% after 24 months.

3.9 Akbarnia et al. (2013b) reported on a retrospective matched case series involving children with early-onset scoliosis: 12 treated with the MAGEC system rods and 12 treated with conventional growth rods, in 5 centres worldwide. The 12 children in the MAGEC system group were included in the Ellipse (2013) study and were therefore not included in the sponsor's evidence synthesis. This study is summarised here because it is the only study that compared the MAGEC system against conventional growth rods. The children were matched by disease type, sex (when possible), age, degree of curvature and receipt of single or dual rods. Their mean age was 6.8 years in the MAGEC group and 6.6 years in the conventional growth rod group. The mean follow-up time differed between the 2 groups, being 2.5 years in the MAGEC group and 4.1 years in the conventional growth rod group. In the MAGEC group, the Cobb angle changed from a pre-operative (baseline) mean of 59° to 32° immediately post-operatively and 38° at the latest follow-up. In the conventional growth rod group, the mean Cobb angle changed from 60° at baseline to 31° post-operatively and 41° at the latest follow-up. The mean increase in spine height post-operatively was statistically significantly smaller in the MAGEC group compared with the conventional growth rod group (18 mm compared with 41 mm; p=0.04). The mean change in spine height from baseline to final follow-up between the 2 groups was also statistically significantly smaller in the MAGEC group compared with the conventional growth rod group (38 mm compared with 77 mm respectively; p=0.01). Mean annual total spine growth was less in the MAGEC group (7 mm per year) compared with the conventional growth rod group (11 mm per year), but this difference was not statistically significant. The authors suggested that the initial surgery could have contributed to the difference in increase in total spine height from baseline to final follow-up, which could be a result of differences in surgical technique across the participating sites. Children in the MAGEC group needed 4 revision operations compared with 17 for those in the conventional growth rod group. In the MAGEC group, 14 complications occurred, of which 10 were implant-related; in the conventional growth rod group, 23 complications occurred, of which 15 were implant-related. Children in the MAGEC system group had fewer surgical site infections (1 compared with 3).

3.10 Yoon et al. (2013) reported on a retrospective case series evaluating pulmonary function in 6 children with early-onset scoliosis secondary to neuromuscular disease treated with the MAGEC system in a UK hospital. The mean age at the time of surgery was 7.5 years and mean follow-up was 2.5 years. Pulmonary function tests were carried out before and after the insertion of the MAGEC rods and at each distraction. The authors reported that the severity of lung function deficit for 2 of the children treated meant that they would not have been able to receive conventional growth rods, but no further details of the children's condition were provided. Other outcomes measured were Cobb angle, amount of rod lengthening and total spine height, but these results were included in the study by Dannawi et al. (2013). Dual rods were implanted in 5 of the 6 children. An average of 7 distractions per child was carried out during the study period. Forced vital capacity (FVC) increased from 27% to 41% of predicted value[1] (p=0.028) and forced expiratory volume in 1 second (FEV1) increased from 27% to 45% of predicted value (p=0.027). Coronal and sagittal Cobb angle, thoracic kyphosis and spine height all showed improvement and the authors reported a moderate positive trend between the amount of distraction and the observed improvement in FVC.

3.11 The sponsor carried out meta- and qualitative analyses of the clinical evidence, including 4 studies of the MAGEC system (Akbarnia et al. 2013a; Cheung et al. 2012; Dannawi et al. 2013 and Ellipse 2013) and 1 study (Bess et al. 2010) which evaluated complication rates for 140 children treated with conventional growth rods. The conventional growth rod arm of the study by Akbarnia et al. (2013b) was also included. The outcomes considered in the meta-analysis were Cobb angle, and thoracic and total spine heights. Qualitative analysis was carried out on infection rates, number of operations, distraction rates and device failure.

3.12 In addition to the adverse events reported in the clinical evidence, the sponsor described 12 adverse events in its submission that had been reported to regulatory agencies. These 12 events related to broken or malfunctioning rods and resulted in 4 revision operations. The External Assessment Centre sought clinical expert opinion on the relative safety of the MAGEC system compared with conventional growth rods; the experts did not describe any significant safety concerns.

3.13 The External Assessment Centre carried out revised meta- and quantitative analyses, in order to consider a broader range of evidence on conventional growth rods. The External Assessment Centre carried out a systematic literature review including data from 15 studies on conventional growth rods, along with the conventional growth rod arm of the Akbarnia et al. (2013b) study. The analyses included the same 4 MAGEC system studies used by the sponsor.

3.14 The External Assessment Centre noted several differences between the populations in the MAGEC system studies and the conventional growth rod studies at baseline, including a lower mean Cobb angle (65.7° and 72.4° respectively), a greater mean total spine height (288 mm and 258 mm respectively) and a difference in mean age at the time of rod insertion (8.0 years and 6.4 years respectively). The External Assessment Centre considered that these differences were likely to have influenced the potential change in each outcome over time. For example, greater height at baseline may limit the potential for growth during follow-up. Similarly, a less severe Cobb angle may limit the potential for improvement in Cobb angle measurement. Inclusion criteria in the conventional growth rod studies varied, with some using Cobb angle and others using age or progression of disease. Dual rods were used in approximately 64% of children involved in the study. Mean duration of follow-up was 4.3 years, which is longer than that of any of the MAGEC system studies (mean 2.5 years). However, the External Assessment Centre considered the studies to be sufficiently homogenous in terms of population, intervention, setting, study design and outcomes to be included in a meta-analysis.

3.15 The conventional growth rod studies were considered in 2 groups, depending on the duration of follow-up: less than 38 months or 38 months and over. The period of 38 months was selected after considering the mean and range of follow-up times. The aim was to allow a more direct comparison with the shorter follow-up in the MAGEC system studies. The outcomes considered were Cobb angle, total spine height and infection rate. Heterogeneity was measured for each outcome and results from fixed and random effects models were presented. All 4 MAGEC system studies were included in the meta-analysis for each outcome, but conventional growth rod studies were only included if they provided usable data for the particular outcome. Quantitative analysis was conducted for the number of surgical procedures (per child and per year), rate of distraction and rate of device failure.

3.16 Findings from the External Assessment Centre's revised meta-analysis and quantitative analysis are presented in tables 1 and 2. The mean change in Cobb angle from baseline was 27° for the MAGEC system studies and 32° for the conventional growth rod longer follow-up studies, with low heterogeneity between studies. The External Assessment Centre considered that the figures for these 2 groups were unlikely to be comparable because of the difference in follow-up time. The shorter follow-up study reported a mean change in Cobb angle of 37°, but this showed variation from the other conventional growth rod studies. The MAGEC studies showed a mean change in total spine height of 4.55 cm with very low heterogeneity. Heterogeneity was very high between the conventional growth rod studies, indicating clinical or methodological diversity across the studies and so limiting the usefulness of the results. There were also differences in age range between the studies. The mean change in total spine height was 6.43 cm for the longer follow-up group and 10.76 cm for the shorter follow-up group. The MAGEC studies showed moderate heterogeneity and a mean infection rate per patient of 3–4%. The infection rates in the conventional rod groups varied from 3–17%, but these rates were complicated by limited reporting in the included studies, with uncertainty around the type of infection included.

3.17 Results of the External Assessment Centre's revised quantitative analysis showed that the number of surgical procedures per child was less in the MAGEC system group (1.2) than in both the shorter and longer follow-up conventional growth rod groups (4.3 and 5.8 respectively). Calculated annual procedure rates per child (including initial surgery) were 0.9 for the MAGEC system group and 1.5 and 1.1 for the shorter and longer follow-up conventional growth rod groups respectively. The mean number of distractions per child was higher in the MAGEC system group than in the conventional growth rod groups, at 6.2 compared with 4.2 (shorter follow-up) and 4.6 (longer follow-up). The only type of device failure reported was rod breakage. The mean rates of device failure per child were lower in the MAGEC system group than in either conventional growth rod group (MAGEC 6%, shorter follow-up conventional growth rods 13%, longer follow-up conventional growth rods 31%). The annualised rates were around 4.5% in the MAGEC system and shorter follow-up conventional growth rod groups and 7.2% in the longer follow-up conventional growth rod group. The External Assessment Centre noted that these results may reflect the more frequent use of single rods rather than dual rods in the past, which are known to have a higher risk of failure. It noted that results may also have been influenced by advances in rod design, mainly relating to the use of stainless steel rods in the past compared with the stronger titanium rods currently used.

Table 1 Results of the External Assessment Centre's revised meta-analysis

Number of studies included

Heterogeneity I 2*

Fixed effects model or single study (mean, lcl–ucl)

Random effects model (mean, lcl–ucl)

Cobb angle (º)

MAGEC system

4

44.89

27.16
(24.41–29.92)

27.17
(23.12–31.22)

CGR shorter follow-up

1

N/A (1 study)

37.03
(27.26–46.80)

CGR longer follow-up

4

34.83

32.14
(28.91–35.36

32.90
(28.61–37.18)

Change in total spine height (cm)

MAGEC system

4

0

4.55
(3.98–5.11)

4.55
(3.98–5.11)

CGR shorter follow-up

2

92.33

12.29
(11.16–13.43)

10.76
(5.53–15.98)

CGR longer follow-up

3

96.5

4.25
(3.77–4.72)

6.43
(2.70–10.15)

Infection rates (% per patient)

MAGEC system

4

61.68

0.03
(0.00–0.08)

0.04
(0.00–0.15)

CGR shorter follow-up

2

83.75

0.03
(0.00–0.08)

0.03
(0.00–0.25)

CGR shorter follow-up (Zhao et al. [2012] study only)

1

N/A (1 study)

0.12
(0.03–0.31)

CGR longer follow-up

8

57.33

0.14
(0.11–0.16)

0.15
(0.11–0.20)

CGR longer follow-up (without Kabirian [2012a] study)

7

38.74

0.16
(0.13–0.20)

0.17
(0.13–0.21)

*Values for measuring heterogeneity between studies: <50% is low, 50–70% is moderate and >70% is high

CGR, conventional growth rods; lcl, lower confidence interval; ucl, upper confidence interval

Table 2 Results of the External Assessment Centre's revised quantitative analysis

Number of patients

Total number of outcomes

Mean per patient

Mean per patient per year

Average interval

Surgical procedures

MAGEC

80

95

1.2

CGR shorter follow-up

78

336

4.3

CGR longer follow-up

264

1523

5.8

Distractions

MAGEC

80

496

6.2

4.5

2.3

CGR shorter follow-up

30

125

4.2

1.4

8.6

CGR longer follow-up

555

2557

4.6

1.1

9.2

Device failure

% per patient

MAGEC

80

5

6.3%

CGR shorter follow-up

103

13

12.6%

CGR longer follow-up

808

254

31.4%

CGR, conventional growth rods

Committee considerations

3.18 The Committee considered that the clinical evidence was limited because it was restricted to small observational studies, and so was insufficient in quantity or quality to establish clinical superiority of the MAGEC system compared with conventional growth rod systems for lengthening the spine and reducing spinal curvature in children with scoliosis. However, it judged that the evidence provided by the various studies, taken together with clinical expert advice, was sufficient to demonstrate the clinical non-inferiority of the MAGEC system with the conventional growth rod systems.

3.19 The Committee was advised that the population of children with scoliosis is heterogeneous, because scoliosis has multiple causes and children may have different comorbidities and magnitudes of curvature. The Committee considered that this was an important confounding factor in the clinical studies. The Committee also noted that the differences in baseline characteristics such as age, Cobb angle and spine height between the children treated with the MAGEC system and conventional growth rods in the available clinical studies could have affected the results. The Committee was advised that the age at which growth rods are first inserted will affect the growth potential of the child's spine, with younger children having more growth potential than older children.

3.20 The Committee was advised that the MAGEC growth rods are functionally similar to conventional rods and are attached to the spine in the same way. It was also advised by experts that the initial reduction in Cobb angle at the time of insertion of growth rods should be similar for the 2 systems. The Committee noted that the External Assessment Centre's review of the clinical evidence indicated that the device failure rate of the MAGEC system rods was at least equivalent to that of conventional growth rods.

3.21 The Committee was advised that Cobb angle and spine height are often difficult to measure and are subject to variation in interpretation when viewing images of the spine. Nevertheless, experts stated that these measures are currently the most reliable indicators of changes in spinal curvature and growth of the spine for children with scoliosis.

3.22 The Committee judged that, because of the uncertainty around the clinical evidence and the available measures, a system for capturing data on individual cases – such as a register – would be useful to expand the evidence base for the use of growth rods, including the MAGEC system. Experts stated that a British Spine Registry was set up by the British Association of Spinal Surgeons in 2012, and it is hoped that this will include data on children with scoliosis. The Committee thought that this would be very valuable in view of the clinical data uncertainties.

3.23 The Committee considered that the MAGEC system had significant potential to improve quality of life for children needing surgical treatment for scoliosis and for their families or carers. In particular, it noted the benefits associated with avoiding the repeated surgical procedures for lengthening conventional growth rods. These included outcomes such as less pain, less time in hospital and less time away from usual activities, as well as a reduced risk of infection and less scarring. In addition, the Committee noted the potential for less psychological distress, mainly fear and anxiety about the lengthening procedures. The Committee heard patient expert contributions describing the positive attitude of children going to hospital for distraction procedures with the MAGEC system, compared with the distress they experienced when attending for surgical lengthening of conventional growth rods. The Committee was told that grouping outpatient appointments together for children with the MAGEC system rods can not only enhance efficiency (because the external remote control can be used for a number of children in a single clinic), but has the additional benefit of allowing the children to interact, reducing their sense of isolation.

3.24 The Committee recognised that the MAGEC system offers the possibility of more frequent and gradual distraction of the spine than conventional growth rods. The Committee heard clinical expert advice that the optimal frequency of distractions and the amount of lengthening done at each appointment remains uncertain and that practice is evolving: specifically, the frequency of distractions may increase in future. The Committee was clear that any increase in the frequency of distractions would need to take into account the increased radiation exposure from multiple imaging procedures (see section 3.27).

3.25 The Committee noted that the MAGEC system may offer particular advantages for some children who are at high risk from repeated surgical procedures, by removing the need for those procedures and the associated risk of complications. The Committee was also advised that the MAGEC system may provide an option for children for whom treatment with growth rods would otherwise be considered unsuitable because of the risks from repeated surgical lengthening procedures. This may offer benefits to those children (in terms of their quality of life) and to the healthcare system (in terms of less need for treatment of associated conditions, such as chest infections). However, this group was outside the scope of this evaluation.

3.26 The Committee heard clinical expert advice that the MAGEC system may be unsuitable for use in children with severe kyphotic curves, because a flat section of spine is needed for distraction with the MAGEC system. The Committee considered that the decision to use the MAGEC system or conventional rods would depend on the individual child's condition and the wishes of the child and their family, after careful discussion of the available options.

3.27 The Committee considered the potential impact of additional imaging associated with more frequent distractions. The Committee was advised that X-rays were not always used after each distraction and that ultrasound may be an option for more frequent distractions. The Committee was also advised that the use of magnetic resonance imaging (MRI) is currently contraindicated for children with MAGEC system rods in place, but that research is in progress to determine whether any level of MRI can be carried out safely and effectively in these children. The Committee considered that further evidence should be developed about the relative merits of X-rays, MRI and other imaging techniques such as ultrasound in children being treated with the MAGEC system.



[1] The test result is often shown as a percentage of the 'predicted values' for patients of similar characteristics. A result close to 100% is considered to be normal, although results over 80% are often also considered normal.

  • National Institute for Health and Care Excellence (NICE)