Evidence review

Advice

Clinical and technical evidence
Clinical evidence
Costs and resource consequences
Strengths and limitations of the evidence

Evidence review

Clinical and technical evidence

Regulatory bodies

There have been no Field Safety Notices or Medical Device Alerts issued by the Medicines and Healthcare Products Regulatory Agency (MHRA) for the OnControl system.

A search of the Manufacturer and User Device Facility Experience (MAUDE) database identified 4 adverse event reports that have been submitted to the US Food and Drug Administration (FDA) in relation to the OnControl system. Two events were associated with the breaking of the biopsy needle during the procedure, 1 event was a case of excessive bleeding, and 1 involved inappropriate needle insertion that led to lower quadrant pain, decreased blood pressure and decreased heart rate. It appears that no events had any lasting effect on patient quality of life.

Clinical evidence

The best quality clinical evidence was 1 systematic review and meta‑analysis (Voigt et al. 2013), which is summarised in table 1. This review included 5 randomised controlled trials (Berenson et al. 2011, Bucher et al. 2013, Miller et al. 2011, Reed et al. 2011 and Swords et al. 2011) identified from the literature search, and adopted appropriate statistical techniques to synthesise the individual results. Of the 5 studies, 1 was set in Switzerland (Bucher et al. 2013), 1 in Spain and the USA (Swords et al. 2011), and the others in the USA only. Three studies were of bone marrow biopsy procedures only (Berenson et al. 2011, Bucher et al. 2013 and Miller et al. 2011), and Reed et al. 2011 and Swords et al. 2011 included bone marrow aspirations, together with biopsies. The results from the aspiration procedures were not synthesised.

Table 1 Summary of the Voigt et al. (2013) systematic review and meta‑analysis

Study component	Description
Objectives/hypotheses	To determine whether the OnControl powered bone marrow biopsy system provides significantly different/improved outcomes on the endpoints of pain and sample length.
Study design	Systematic review and meta‑analysis.
Inclusion/exclusion criteria	RCTs comparing the powered system with manual biopsy methods were included. Patients with blood and bone marrow conditions were included.
Primary outcomes	Pain as measured using a VAS 100‑point scale. Bone marrow trephine biopsy length (in mm) and volume (in mm³). Operator satisfaction. Complications or adverse events.
Statistical methods	For continuous data, the mean difference (inverse variance, random or fixed‑effects model) was used, and for binary outcomes risk ratios were presented (Mantel–Haenszel, random or fixed‑effects model). Each central estimate had corresponding 95% CIs and p values. Statistical heterogeneity was measured using the I² statistic; if an I² was 60% or less then meta‑analysis was deemed appropriate. Funnel plots were used to assess reporting bias.
Participants	Five RCTs met the criteria, with 318 patients (n=160 in powered arm and n=158 in manual arm).
Results: pain at needle insertion, measured as mean VAS score from 0–100 with 100 being maximal pain	Powered: 25.9 (n=101)^a Manual: 33.8 (n=99) Mean difference 7.9, 95% CI −15.8 to 0.0, p=0.05
Results: overall pain, measured as mean VAS score from 0–100 with 100 being maximal pain	Powered: 32.4 (n=158)^a Manual: 39.0 (n=156). Mean difference 6.6, 95% CI −12.9 to −0.2, p=0.04
Results: biopsy length (mm)	Powered: 14.5 mm (n=158)^a Manual: 10.9 mm (n=156) Mean difference 3.6 mm, 95% CI −15.8 to 0.0, p<0.001
Results: biopsy volume (mm³)	Powered n=77 Manual n=75 Absolute values not reported Mean difference 18.3 mm³, 95% CI 13.3 to 23.3, p<0.001
Results: operator satisfaction, measured as mean VAS score from 0–10 with 10 being highest satisfaction	Powered n=77 Manual n=75 Absolute values not reported Mean difference 1.4, 95% CI −0.75 to 3.56, p=0.20, I²=95%
Results: number of adverse events	Powered: 4/160 (2.5%) Manual: 0/158 (0.0%) Risk ratio 3.6, 95% CI 0.6 to 21.4; p=0.17
Conclusions	The results demonstrate statistically significant lower pain scores, improved sample sizes, slightly higher complications and adverse events and a similar level of operator satisfaction for the powered system compared with the manual methods.
Abbreviations: CI, confidence interval; mm, millimetre; RCT, randomised controlled trial; VAS, visual analogue scale. ^a Mean values were not explicitly reported within the article, but were calculated using information presented within forest plots.

The findings show statistically significant reductions in pain scores and statistically significant increases in biopsy lengths and volumes.

The systematic review did not report data on the adequacy of samples for diagnostic purposes, the duration of procedures or patient satisfaction. The results for each of these end points are discussed below and included by study in table 2.

Three of the randomised controlled trials included in the systematic review reported on the adequacy of samples for diagnostic purposes. Berenson et al. (2011) reported that the overall quality of the biopsy sample was rated adequate for 78% of the powered and 70% of the manual samples (p=1.00). Bucher et al. (2013) also reported no statistically significant difference in biopsy quality, which was rated 'sufficient for diagnosis' in 83% of the powered group and 80% in the manual group (p=0.74). Miller et al. (2011) reported that 79% of samples from powered systems and 33% from manual systems were graded adequate for pathology (p=0.002). No study directly measured whether the OnControl system reduced the number of repeat biopsies needed because of inadequate samples taken in the initial procedure.

Procedure duration was not reported in the systematic review because of high heterogeneity across the studies. Four of the 5 studies reported a statistically significant shorter mean procedure time for the powered group, and Bucher et al.(2013) reported that the procedure time tended to be shorter with the OnControl system. Evidence from a separate prospective study (Tanasale et al. 2011, not presented in the tables) found that procedure duration is correlated positively with pain.

Berenson et al. (2011) and Bucher et al. (2013) reported patient satisfaction. Patients were satisfied with both the OnControl system and manual bone marrow biopsy, scoring 9.4 out of 10 for the OnControl system and 9.3 out of 10 for manual biopsy in the study by Berenson et al. (2011), and a median of 9 for both groups in Bucher et al. (2013). Bucher et al. also reported satisfaction in patients who did not have sedation (n=15). There was a significant difference in this group, with the OnControl system scoring a median of 7 compared with 3 for the manual biopsy (p=0.015). Reed et al. (2011) reported a significant difference in patients willing to have a repeat procedure with the OnControl system compared with the manual biopsy (p<0.03).

Table 2 Summary of end points in the 5 RCTs that were not included in the systematic review and meta-analysis by Voigt et al. (2013)

	OnControl system		Manual biopsy	Analysis
Using a powered bone marrow biopsy system results in shorter procedures, causes less residual pain to adult patients, and yields larger specimens (Berenson et al. 2011)
Design	Multi‑centre (10), randomised, non‑blinded, controlled trial
Randomised (if applicable)	n=52		n=50
Efficacy	n=52		n=50
Key end points not used in Voigt et al. (2013)
Overall quality of core biopsy rated adequate	77.8% (40/52)		70.0% (35/50)	p=1.000
Core acquisition time; mean and SD	102±85 seconds		203±150 seconds	p=0.001
Patient satisfaction (0–10); mean and SD	9.4±1.2		9.3±1.6	p=0.778
Comparison of a powered bone marrow biopsy device with a manual system: results of a prospective randomised controlled trial (Bucher et al. 2013)
Design	Prospective, single‑centre, randomised, non‑blinded, controlled trial
Randomised (if applicable)	n=24		n=26
Efficacy	n=24		n=26	Note that there were 30 procedures in each group, with 8 patients having 2 procedures and 1 patient having 3.
Key end points not used in Voigt et al. (2013)
Biopsy quality sufficient for diagnosis	83.3% (25/30)		80.0% (24/30)	p=0.74
Procedure time duration; median (range)	150 (60–720) seconds		180 (80–480) seconds	p=0.95
Median (range) patient satisfaction VAS (0–10, low–high) in all patients	9 (0–10)		9 (3–10)	p=0.69
Median patient satisfaction VAS without sedation	7 (n=9)		3 (n=6)	p=0.015 Range not reported.
Powered bone marrow biopsy procedures produce larger core specimens, with less pain, in less time than with standard manual devices (Miller et al. 2011)
Design	Single‑centre, randomised, non‑blinded, controlled trial
Randomised	n=26		n=26	Each participant had a procedure from each device
Efficacy	n=24		n=24	Two patients were excluded due to inadequacies in the procedure
Key end points not used in Voigt et al. (2013)
Pathology‑graded adequate biopsy core	79.2%		33.3%	p=0.002
Mean time to core acquisition	46.5±15.8 seconds		85.7±31.0 seconds	p<0.001
The OnControl bone marrow biopsy technique is superior to the standard manual technique for haematologists‑in‑training: a prospective, randomized comparison (Reed et al. 2011)
Design		Single‑centre, randomised, non‑blinded, controlled trial (randomisation was of operators not patients)
Randomised		n=54 patients, 27 in each arm but not randomised; 11 operators were randomised to technique and patient
Efficacy		n=27	n=27
Key end points not used in systematic review and meta‑analysis Voigt et al. (2013)
Procedure time, mean and SD		175±105 seconds	292±210 seconds	p=0.007
Patient willingness to have repeat procedure, score 0 to 10 high to low, mean and SD		1.0±2.2	2.9±3.5	p<0.03
A prospective randomised study of a rotary‑powered device (OnControl) for bone marrow aspiration and biopsy (Swords et al. 2011)
Design	Multi‑centre (2), randomised, controlled trial
Randomised	n=25		n=25
Efficacy	n=25		n=25
Key end points not used in Voigt et al. (2013)
Core biopsy usable area, mean and SD	25.4±12.3 mm²		11.9±5.6 mm²	p=0.001
Biopsy procedure time, mean and SD	100.0±72.8 seconds		224.1±79.0 seconds	p≤0.001
Abbreviations: SD, standard deviation; VAS, visual analogue scale.

Recent and ongoing studies

One recently completed trial comparing the OnControl system with manual bone marrow examination in children was identified in the preparation of this briefing. This trial compared the use of the OnControl device (n=22) with a manual device (n=22) for bone marrow examination. Results are available on Clinicaltrials.gov (identifier: NCT02159118) and are summarised in table 3.

Table 3 Results from a study comparing manual and powered bone marrow aspiration and biopsy devices in children

	OnControl powered	Manual procedure	Analysis
A study comparing use of manual and power bone marrow aspiration and biopsy devices in children
Design	Single‑centre, randomised controlled trial
Randomised	n=22	n=22
Efficacy	n=22	n=22
Selected outcomes (primary outcome listed first, then secondary outcomes)
Percentage of hematopoietic tissue present; mean and SD	55.8±19.4	42.5±21.8	p=0.03
Biopsy volume; mean and SD	36.5±16.1 mm³	23.8±11.5 mm³	p=0.01
Biopsy length; mean and SD	13.4±4.7 mm	13.9±3.4 mm	p=0.65
Time for procedure; mean and SD	53.2±30.5 seconds	55.0±34.1 seconds	p=0.22
Overall procedure pain score rated from 0–10 with 10 being maximal pain; mean and SD	0.68±1.36	0.27±0.94	p=0.93
Operator satisfaction rated 0–10 with 10 highest; mean and SD	9.2±1.0	9.0±1.0	p=0.51
Abbreviations used: SD, standard deviation.

This is the only study of the OnControl system in children, and the only one of all the studies reporting a lower pain score and higher sample length with the manual device.

Costs and resource consequences

No published evidence on resource consequences was identified.

The manufacturer states that the OnControl system is currently used in 6 NHS Trusts in England and Wales. No changes to current service organisation or delivery are expected if the OnControl system is adopted in the wider NHS. The manufacturer does not recommend using this system for bone marrow trephine biopsy in children, so they will still need manual biopsies. No additional facilities or technologies are needed alongside the OnControl system.

Clinical evidence suggests some patients may find the OnControl system less painful than a manual device. Should these patients need a second examination then there may be a reduction in requests for sedation and lower costs to the NHS. However, there is no substantial evidence from the studies to support this claim.

In clinical practice, some patients may need a second procedure if the original sample is not good enough for accurate diagnosis. Bucher et al. (2013) aimed to measure if the powered device would produce larger biopsies and therefore help to avoid 'non‑diagnostic' biopsies, but found no difference in the diagnostic quality of samples from the OnControl system or manual biopsy. Berenson et al. (2011) did find a non‑significant, higher absolute level in the percentage of usable samples with the OnControl system (78% compared with 70%). If this result is replicated in clinical practice then it may be possible to avoid some repeat procedures, improving patient experience and efficiency.

Strengths and limitations of the evidence

The principal evidence source was the systematic review and meta‑analysis by Voigt et al. (2013). This was judged to be of high quality. The literature search was rigorous, and study selection and data extraction was done by 2 people acting independently. Clear inclusion criteria were applied, bias was assessed in each included study, publication bias was checked for and the methods used to synthesise the data were robust. Heterogeneity across the studies was assessed to inform when synthesis was valid, and the results from the random effects models were presented using forest plots.

All 5 studies in the systematic review had similar limitations. In particular, allocation was not adequately concealed and neither patients nor operators were blinded to the choice of intervention during the procedure. However, given the nature of the procedure it is difficult to ensure blinding. The study by Miller et al. (2011) attempted to ensure that the patients were blinded to the intervention, but it is not clear if the technique used was effective. All trials were also at risk of performance bias, because operators were experienced users of the manual device but had minimal experience with the OnControl system. Finally, all of the trials were conducted outside the UK, so it is unclear how generalisable the results are to the NHS.

Strengths of the studies include that all of them were randomised, reducing selection bias. The only differences reported between arms were the devices themselves, with the operators, patient preparation, education and after‑care being the same across the groups, reducing other forms of performance bias. All studies had a low rate of attrition, with only 2 patients excluded from the intention‑to‑treat population. These were in the study by Miller et al. (2011), and a rationale for the exclusions was provided.

The definition and approach to measuring outcomes was reasonably consistent across all studies except for the study by Miller et al. (2011). This study had a potential detection bias in recording pain, as patients in the study re‑scored the first procedure for pain after recording the pain associated with the second procedure. This study was conducted with volunteers rather than patients who needed a bone marrow examination for clinical purposes. Because of this, patients may have had a different perception of pain, particularly since they knew they would not need a repeat procedure at a later date. Differences in the populations recruited on other studies included the use of sedation, and 1 study (Bucher et al. 2011) excluded patients with a BMI over 35.

Reed et al. (2011) had a different aim from the other studies. It was set in a teaching hospital and designed to answer whether manual or powered procedures were superior for training haematology students in biopsy practice. Because of this, operators were randomised instead of patients. In addition, the study only used length of sample as a surrogate for biopsy quality, whereas the other studies also considered width or volume of sample.

Bucher et al. (2011) is the only study which was conducted without funding from the manufacturer. None of the authors of this study had any conflicts of interest.