The present report provides a single technology assessment of EXOGEN™ for the treatment of non-union fractures. We did not identify any studies comparing directly EXOGEN™ to other treatment alternatives, foremost surgery, nor sham. Thus, there was not available relevant evidence to assess the clinical effectiveness of this technology compared to alternative treatments which in turn affected the basis for a health economic analysis. In conclusion, there is a need for improved evidence, preferably a randomised controlled clinical trial to assess the clinical effectiveness of EXOGEN™ compared to a relevant alternative.
Most fractures heal within estimated time lines. However, between 5% and 10% of all fractures go on to a delayed (no radiological evidence of healing after approximately three months) or non-union (failure to heal after nine months) state. The current treatment option in Norway for non-union fractures is surgical treatment.
EXOGEN™ is a Class IIa Medical Device. It has a CE-certificate and is approved of the Premarket Approval Application (PMA) of the Food and Drug Administration (FDA). It is also approved in UK (NICE), Australia, Canada, Japan and United States of America.
EXOGEN™ is designed to use low-intensity pulsed ultrasound (LIPUS) to help stimulate the body’s natural healing of a fracture. The device is portable and self-administered by the patient for 20 minutes per day.
Patient series have suggested that LIPUS might promote healing of non-union fractures. A recent systematic review of randomised trials for bone healing concluded that based on moderate to high quality evidence from studies in patients with fresh fracture, LIPUS does not improve outcomes important to patients and probably has no effect on radiographic bone healing. The applicability to other types of fracture such as non-union fractures is open to debate.
This single technology assessment was commissioned by the Commissioning Forum in the National System for Managed Introduction of New Health Technologies within the Specialist Health Service in Norway (ID2015_014). The Forum requested the Norwegian Institute of Public Health to evaluate the efficacy, safety and health economic documentation for EXOGEN™ compared to surgical treatment for the management of patients with non-union of a fracture. Norwegian Institute of Public Health has evaluated the submitted documentation up towards available published documentation.
Evaluation of the documentation
The submitted documentation for efficacy and safety came from literature identified by searching PubMed using relevant terms. Their search was limited from January 1 1992 to October 31 2015. Articles written in English and available in full text were appraised for inclusion.
Although PubMed is a large medical database, searching only in one database is considered insufficient. Norwegian Institute of Public Health systematically searched for literature related to EXOGEN™ in Embase, MEDLINE, Cochrane Library, PubMed and WHO ICTRP. We conducted an updated search February 2018. Two of the twelve studies included in the submission dossier are excluded from this single assessment report, since these studies did not include patients with non-union fractures, but only patients affected by delayed union fractures. From these ten publications, we have reviewed the efficacy endpoints described by the submitter: healing rate, healing time and treatment failure related to both treatment arms, and adverse events as infection rate related to surgery treatment. We also presented a propensity-matching study focusing on delayed union factures, four systematic reviews focusing on various fracture sites and different types of fractures, and an article presenting several case series.
The endpoints related to surgery are based on the submitted search in PubMed. The submitter found 19 various studies about surgical treatment of patients affected by non-union fractures.
We evaluated the quality of the evidence for EXOGEN™ treatment by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, and by reading the submitted descriptions of the surgery studies.
Health economic documentation
The submitter performed a cost-effectiveness analysis where the ultrasound bone healing system for the treatment of non-union fractures – EXOGEN™ – was compared with standard surgery. The analysis adopted a simple Markov approach based on a 1-year time horizon and monthly cycles. The model contained four health states: not healed (non-union fracture), healed fracture, minor infection and deep infections (osteomyelitis). Patients in the EXOGEN™ pathway have EXOGEN™ as baseline treatment and patients in the surgery pathway have surgery as baseline treatment. In both pathways, if healing has not occurred within six months, it is assumed that further surgery is performed. After the surgical treatment, patients are at risk of infection.
In addition to presenting results calculated by the submitter, we have assessed the submitted documentation by making comments in each section.
The quality of the evidence
Neither Bioventus nor we have identified studies of high quality. Our confidence in the results is therefore very low, and we cannot conclude regarding the effects of EXOGEN™ compared to surgery for patients with non-union fractures, nor sham. Thus, we are not able to assess the cost-effectiveness of EXOGEN™ compared to alternatives. Here we report the results based on the documentation package from Bioventus, and our own literature searches and evaluations.
Healing rate and healing time:
Based on the submitted literature in the documentation package, the submitter estimated a healing rate to be about 86% for patients getting treated by EXOGEN™. The mean healing time by getting EXOGEN™ treatment was considered by the same studies used to decide the healing rate. The submitter considered that the healing time would be about six months when the healing rate is 86%. The submitter considered that the mean healing rate and healing time for surgical treatment would be the same as for EXOGEN™ treatment, because the healing rates of the included studies varied between 74% and 100% at six months at six months.
Adverse events: The submitter stated that the EXOGEN™ treatment has no known device related adverse events. However, the individual studies have reported major complications with surgery. The complications includes deep vein thrombosis, deep and superficial infections (1.2% infection rate), hematoma and poor range of movement. Longer term complications included requirement for further surgery (hardware removal), persistent non-union and in the case of bone grafting persistent donor site pain. Even in the case of achieving union of fractures through surgery, removal of metalwork added further surgical intervention to patient management. Regarding the radiation exposure, the submitter stated that the use of EXOGEN™ represents an opportunity to reduce exposure to radiation.
Treatment failure: Both treatment options are presumed to give the same healing rate at about 86% at the same healing time, six months. That means that 14% of the patients in both treatment options would fail to heal within six months. In both strategies further surgery is required.
Based on the limited documentation and absence of comparative studies nor randomized controlled trial between EXOGEN™ treatment and surgery, we are very uncertain about the effect of LIPUS compared with surgery. Expert opinion suggested that the infection rate at 1.2% was somewhat too low, and that a more reliable rate would be between 1% and 4%. Expert opinion suggested that radiographs are necessary in both treatment options.
Health economic results
The submitted basecase suggested that the technology is dominant for individuals with non-union fracture, i.e. that EXOGEN™ is a cheaper and more effective technology than surgery. The submitter found that the magnitude of the estimated cost-difference declines as surgery becomes more effective than EXOGEN™. This is because EXOGEN™ is a considerably cheaper product than a surgical procedure.
The submitter calculated in their budget impact analysis potential cost savings by introducing EXOGEN™ in Norway. The submitter assumed that the maximum patient share (30% of the patients with non-union fractures) will be reached within four years, and that it will be cost savings each year by adopting EXOGEN™. They estimated that the total cost savings for year three after adoption of EXOGEN™ in Norway would be about NOK 2,684,753.
We noticed that the budget impact model created by the submitter did not consider the total patient costs. By only using the EXOGEN™ device cost or the one time surgical treatment cost, they did not take into account infections that may occur in both arms if the individuals are “not healed”.
Bioventus has submitted documentation supporting the literature search and their presentation of the evidence. However, neither the submitter, nor we, identified any studies that directly compared EXOGEN™ to other treatment alternatives for patients with non-union fractures, foremost surgery as the standard treatment option today, nor sham treatment. This means that none of the included studies met our PICO requirements. We also missed a critical appraisal from the sponsor of the quality of the evidence for the specific endpoints (GRADE).
There are reported data for efficacy and safety up to six months and 12 months respectively. These time periods are relatively short. We lack evidence on outcomes important to patients. There is no generally accepted definition of fracture healing. Several of the studies only reported radiological criteria, which is insufficient to assess clinical efficacy. Furthermore, all the available evidence came from ten observational studies concerning EXOGEN™ treatment, and 18 observational studies concerning surgical treatment and one RCT comparing surgery with shockwave treatment. This is the main reason why we considered our certainty in the evidence for the specific endpoints to be very low. The present documentation does not give evidence to assess the clinical effectiveness of EXOGEN™ for the treatment of non-union fractures compared to surgery, nor sham.
For new technologies there is a risk of publication bias, since negative studies are less likely to be published than studies showing positive results.
The submitter performed economic evaluation by developing a straightforward model with four health states. We do not think that the submitted health economic model captured the outcomes that are clinically relevant to the defined population and intervention, because the model does not take into account that patients who undergo surgery in the EXOGEN™ arm also may be infected or not infected.
There were some uncertain points to consider regarding the submission. The Norwegian Institute of Public Health finds it difficult to assume that the submitted considered healing rate of 86% for patients with non-union fractures using EXOGEN™ is a reasonable estimate, based on the weak evidence. There is also uncertainty whether a one year time horizon is sufficient to catch up all differences in costs and health outcomes.
Studies using patient history as controls suggest that EXOGEN™ induces healing in non-union fractures. Data from studies examining surgery as the treatment option also indicate that surgery induce healing of non-union fractures. However, as the interventions has not been compared directly in the same study, using the same kind of patients, it is not possible to estimate or conclude on which treatment option has the highest healing rate or fastest healing. Thus, there is no reason to assume equal efficacy. Heterogeneity within the studies for each of the interventions does not favor pooling data to get more precise estimates of effect and safety. In conclusion, the present documentation does not give evidence to assess the clinical effectiveness of EXOGEN™ for the treatment of non-union fractures compared to surgery, nor sham.
The submitted model shows that EXOGEN™ is the dominant treatment. The EXOGEN™ device would in this case be considered cheaper and give higher effectiveness in patients having non-union fractures. However, because of the very low quality of the data on clinical effectiveness, we are unable to assess if EXOGEN™ is cost saving or not, compared to surgical treatment.