Autologous chondrocyte implantation using chondrosphere for treating symptomatic articular cartilage defects of the knee

3.1 The clinical expert explained that the aims of treating symptomatic articular cartilage defects of the knee are to reduce symptoms, restore function and prevent osteoarthritis. The clinical expert confirmed that people with defects will first be offered physiotherapy, corticosteroid injection, pain management and weight loss. If symptoms persist, people will be considered for surgery including knee lavage with or without debridement, microfracture, autologous chondrocyte implantation (ACI) and mosaicplasty. The choice of surgery depends on the size of the defect, condition of the cartilage and other patient-related factors including previous articular cartilage knee repair surgery, age and BMI. The committee understood that in current clinical practice, the preferred surgery for defects larger than 2 cm² would be ACI, provided that the person has minimal osteoarthritis (if any) and no history of previous cartilage repair surgery for the affected knee (see NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee), but that ACI is not widely available (see section 3.3). If symptoms persist after microfracture or ACI, people could have mosaicplasty or further ACI. When all other options have been exhausted, osteotomy, partial and total knee replacement are considered later in the treatment pathway.

3.2 The committee noted that no submissions or expert nominations were received from any patient or professional organisations invited to participate in this appraisal. The clinical expert highlighted that microfracture is commonly used, including for salvage procedures, because it is inexpensive and minimally invasive. However, the expert noted a growing trend of limiting microfracture to smaller defects, with thresholds ranging from 2 cm² to 4 cm². Although NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee recommends ACI for defects larger than 2 cm², the committee noted that there is currently no good surgical alternative to microfracture (see section 3.3). It concluded that there are limited options available for managing articular cartilage defects, particularly those larger than 2 cm².

3.3 The final scope issued by NICE listed a number of comparators, depending on defect size. The committee appreciated that there is variation in the use of these procedures in clinical practice, because of the experience and preference of the treating clinician and the availability of treatment. However, it concluded that the most relevant comparators for this appraisal are microfracture and best supportive care:

3.4 Two trials on chondrosphere used the primary outcome of a 10‑point improvement in overall Knee injury and Osteoarthritis Outcome Score (KOOS) from the day of the surgical procedure:

3.5 Indirect clinical evidence came from a network meta-analysis on the response and failure rates from 3 ACI trials (chondrosphere and 2 other ACI technologies, ChondroCelect and MACI) with microfracture as a common comparator. The ERG was concerned that the 3 trials were severely imbalanced at baseline in several factors that are likely to affect treatment outcomes: defect size, previous articular cartilage knee repair surgery and level of disease burden assessed by KOOS. The committee agreed that it is not appropriate to combine the trials in a network meta-analysis because of these differences. It noted that the ACI comparators (ChondroCelect and MACI) are not relevant to this appraisal because they do not have current marketing authorisation in the UK (see section 3.3). The committee recalled that 'traditional' ACI is available at 1 centre in England, under hospital exemption on a non-routine basis (see section 3.3), but had not been included because there are currently no published data available that enables a network meta-analysis to be done. Therefore, the committee concluded that the most relevant clinical evidence is from COWISI, which provides direct evidence of chondrosphere compared with microfracture.

3.6 The clinical expert confirmed that the minimal clinically important difference in overall KOOS of 8.5 points in COWISI is consistent with clinical practice. The committee noted that chondrosphere is non-inferior to microfracture for all defect sizes (1 cm² to 4 cm²). However, it noted that the improvement from baseline in overall KOOS at 2‑year follow-up was numerically greater in patients who had chondrosphere compared with microfracture. The committee also noted that the difference in overall KOOS between chondrosphere and microfracture was greater for larger defect sizes (2 cm² to 4 cm²) compared with smaller defect sizes (1 cm² to less than 2 cm²). It noted that the proportions of 'responders' (defined as those achieving a 10‑point improvement in overall KOOS) were similar for chondrosphere and microfracture at 2 years. The committee concluded that chondrosphere is at least as effective as microfracture.

3.7 The committee noted that there are little long-term data available on chondrosphere compared with microfracture. It agreed that the phase 2 study (see section 3.4) provides non-comparative evidence of the longer-term effect of chondrosphere at 4 years and in larger defects. It noted that there was continual improvement in overall KOOS from baseline at 1 year and up to 4 years, and the differences were clinically significant. The ERG stated that the benefit of ACI is likely to be seen over the longer term based on observational studies included in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee. The committee agreed that the long-term benefit of chondrosphere is uncertain. However, it concluded that chondrosphere improves outcomes at 4 years and for larger defects.

3.8 The company used a Markov model to assess the cost effectiveness of chondrosphere compared with microfracture and other ACI technologies. It modelled 2 possible treatments in sequence. The model used a lifetime horizon of 100 years, a cycle length of 1 year and transitions between each health state at the end of each cycle. The model population included 60% men and had a starting average age of 33 years. The model was divided into 2 parts, up to and after 55 years:

3.9 The company modelled the same treatment sequences included in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee:

3.10 The committee noted that, like the model in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee, the company's model assumed that after successful microfracture the utility value returns to the baseline value after 5 years (that is, from 0.82 to 0.65). In that appraisal, the committee considered that this was equivalent to assuming that microfracture had failed in all people at year 5. In this appraisal, the clinical expert explained that decline in knee function would likely start at 1.5 years after microfracture. The committee agreed that reducing the utility value for microfracture after 5 years was arbitrary and may have biased the results in favour of ACI. It noted that the company had done a sensitivity analysis in which the utility value of a successful microfracture at 5 years and beyond was maintained at 0.82. The committee understood that removing the assumption that utility decreased over time following a successful microfracture would likely increase the company's base-case incremental cost-effectiveness ratio (ICER). The committee would have preferred the model to adjust for the rate of loss of benefit following microfracture more explicitly, by changing the transition probabilities instead of the utility value of the successful repair health state. In the absence of such analysis, the committee accepted the assumption that there is no further benefit of microfracture after 5 years, but agreed it underestimated the ICER.

3.11 The committee noted the concerns from the ERG about how the company had derived its clinical effectiveness inputs from the network meta-analysis results, which subsequently informed the transition probabilities in the model. The committee noted that these concerns largely affect the other ACI technologies, ChondroCelect and MACI. It noted that a network meta-analysis is not appropriate and that the data from COWISI, which provide direct evidence of chondrosphere compared with microfracture, are preferred (see section 3.5). The committee noted the ERG's scenario analyses using direct evidence from COWISI, and it concluded that these analyses are most appropriate for decision making.

3.12 The ERG explained that it had applied the committee's preferred procedure costs from NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee in this appraisal:

3.13 The committee concluded that the most relevant comparators for this appraisal are microfracture for defects up to 2 cm² and best supportive care for defects larger than 2 cm² (see section 3.3). Therefore, it preferred the following assumptions:

3.14 When microfracture is assumed to return to baseline utility values after 5 years, the ICERs are £4,360 per quality-adjusted life year (QALY) gained for chondrosphere only compared with microfracture only, and £5,294 per QALY gained for chondrosphere followed by chondrosphere compared with microfracture only. The committee noted that there is considerable uncertainty surrounding the ICERs because the long-term benefit of chondrosphere is yet to be established (see section 3.7). It also noted that the low ICERs are largely due to the decline in the utility value for microfracture after 5 years, which underestimates the ICERs (see section 3.4 and section 3.10). The committee was aware that most patients with larger defects are likely to have best supportive care in clinical practice (see section 3.3), and the clinical benefit of chondrosphere compared with best supportive care is likely to be greater than when compared with microfracture. The committee had decided that other forms of ACI are not relevant comparators in this appraisal, because they are not widely available in the NHS (see section 3.3). However, it noted that chondrosphere is cheaper than many of the other ACI technologies appraised in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee (£10,000 for chondrosphere cell costs, compared with £9,300 to £18,300 for the technologies in that appraisal). The committee recalled that the population in COWISI did not have previous knee surgery to repair articular cartilage defects, and agreed that it would be appropriate to only recommend chondrosphere in the same population. Because of the uncertainties related to the comparison with microfracture, the committee agreed that it would be appropriate to recommend chondrosphere only for defects larger than 2 cm². Therefore, the committee applied similar conditions as in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee and concluded that chondrosphere is a cost-effective use of NHS resources for defects larger than 2 cm², in people with no previous surgery to repair articular cartilage defects and minimal osteoarthritic damage to the knee. The committee noted that the recommendation in the technology appraisal on ACI specifies that ACI is only done in a tertiary referral centre. This is because the laboratory that makes the only licensed ACI technology available at the time of that appraisal is affiliated with a tertiary referral NHS orthopaedic hospital. However, the committee agreed that this caveat is not relevant for this appraisal because there is no such constraint on the use of chondrosphere and that removing it would avoid restricting access to treatment. The company stated that although it had not specifically made a case for chondrosphere in the population for which ACI is recommended in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee, it would be satisfied with a similar recommendation.

3.15 The committee agreed that there is an unmet need because currently ACI is not widely available in the NHS, and there are no good alternative surgical options for people with defects larger than 2 cm².

3.16 The company explained that it considers chondrosphere to be innovative. The committee noted that chondrosphere is an improved ACI technology that does not need fibrin glue or a cover flap, and does not include any animal derivatives. The committee considered chondrosphere to be innovative but did not identify any additional health benefits not already included in the economic modelling.

3.17 The committee considered its recommendation in the context of the equality legislation. It was aware that 1 of its criteria for treatment (that is, minimal osteoarthritic damage to the knee) excludes people with advanced or severe osteoarthritis, which can be disabling. However, one of the contraindications in the marketing authorisation for the technology is advanced osteoarthritis. The committee did not stipulate any specific threshold for the level of osteoarthritis, but instead states in the recommendations that it is appropriate for clinicians experienced in investigating knee cartilage damage to assess suitability for chondrosphere using a validated measure for osteoarthritis of the knee. The committee was therefore satisfied that it has mitigated, as far as it can, any potential unfairness.