Autologous Chondrocyte Implantation with Chondrosphere for Treating Articular Cartilage Defects in the Knee: An Evidence Review Group Perspective of a NICE Single Technology Appraisal
Chondrosphere (Spherox) is a form of autologous chondrocyte implantation (ACI). It is licensed for repair of symptomatic articular cartilage defects of the femoral condyle and the patella of the knee with defect sizes up to 10 cm2 in adults. In a single technology appraisal (STA) [TA508] undertaken by the National Institute of Health and Care Excellence (NICE), Warwick Evidence was the Evidence Review Group (ERG) invited to independently review the evidence submitted by the manufacturer, Co.Don. The clinical effectiveness data came from their COWISI randomised controlled trial (RCT), which compared Chondrosphere with microfracture (MF). The timing of this appraisal was unfortunate given that MF was no longer the most relevant comparator because NICE had contemporaneously published guidance approving ACI in place of MF. Moreover, the COWISI RCT enrolled mostly patients with small defect sizes. Evidence of clinical effectiveness for Chondrosphere used in people with larger defect size came from another RCT, which compared three doses of Chondrosphere and that by design could not provide evidence comparing Chondrosphere to any other forms of ACI. To estimate the relative clinical performance of Chondrosphere versus other ACI, Co.Don conducted an indirect treatment comparison by network meta-analyses (NMA). The NMA was flawed in that the distribution of population characteristics that are effect modifiers greatly differed across the treatment comparisons of the network. The ERG questioned both the appropriateness of the NMA and the validity of the resulting estimates. Co.Don estimated the cost-effectiveness of Chondrosphere using a lifetime Markov model with all patients receiving the first repair during the first cycle of the model then moving into one of three health states: success, no further repair (NFR), or a second repair, if necessary. Subsequent to the first cycle, those who were a success either remained a success or moved to second repair. All those in NFR remained in NFR. The cost-effectiveness of Chondrosphere compared to other ACI forms relied on the clinical effectiveness estimates of success and failure rates obtained from the company’s indirect comparisons, the validity of which the ERG questioned. The company revised cost-effectiveness estimates for Chondrosphere versus MF and for Chondrosphere versus matrix-applied characterised autologous cultured chondrocyte implant (MACI) were £4360 and around £18,000 per quality-adjusted life year gained, respectively. NICE recommended ACI using Chondrosphere for treating symptomatic articular cartilage defects of the femoral condyle and patella of the knee in adults only if certain requirements were met.
The views expressed in this report are those of the authors and not necessarily those of the NHS, the National Institute for Health Research (NIHR), the NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC), the HTA programme or the Department of Health. Any errors are the responsibility of the authors.
XA, EC, AM, PR, RJ, JR, NW and HM were authors of the ERG report on which this paper is based. XA, MC and HM produced the first draft of the manuscript. All authors commented on the manuscript and approved the final version. This summary has not been externally reviewed by PharmacoEconomics.
Compliance with Ethical Standards
This project was funded by the NIHR HTA programme (project number 15/69/10). See the HTA programme website (http://www.hta.ac.uk) for further project information: https://www.journalslibrary.nihr.ac.uk/programmes/hta/156910/#/. JR is funded by an NIHR Postdoctoral Fellowship.
Conflict of interest
XA, EC, MC, AM, PR, RJ, JR, NW and HM have no conflicts of interest that are directly relevant to the content of this article.
- 1.International Cartilage Repair Society. ICRS score/grade. 2000. https://cartilage.org/society/publications/icrs-score/. Accessed 25 Jul 2016.
- 2.National Institute for Health and Care Excellence. Autologous chondrocyte implantation with Chondrosphere for treating articular cartilage defects [ID851]. 2017. https://www.nice.org.uk/guidance/indevelopment/gid-ta10162. Accessed 14 Aug 2017.
- 3.National Institute for Health and Care Excellence. Knee cartilage defects - autologous chondrocyte implantation [ID686]: in development [GID-TAG446]. 2017. https://www.nice.org.uk/guidance/indevelopment/gid-tag446. Accessed 15 Aug 2017.
- 4.National Institute for Health and Care Excellence. Autologous chondrocyte implantation for treating symptomatic articular cartilage defects of the knee: technology appraisal guidance [TA477]. 2017. https://www.nice.org.uk/guidance/ta477. Accessed 15 Oct 2017.
- 6.European Medicines Agency. ChondroCelect. 2014. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000878/human_med_000698.jsp&mid=WC0b01ac058001d124. Accessed 25 Jul 2016.
- 7.European Medicines Agency. MACI: matrix-applied characterised autologous cultured chondrocytes. 2014. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002522/human_med_001660.jsp&mid=WC0b01ac058001d124. Accessed 25 Jul 2016.
- 8.European Medicines Agency. Spherox. 2017. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002736/human_med_002138.jsp&mid=WC0b01ac058001d124. Accessed 25 Oct 2017.
- 12.Saris D, Price A, Drogset JO, Podškubka A, Tsuchida A, Bezuidenhoudt M, Kili S, Levine DW, Brittberg M. SUMMIT prospective, randomized, controlled trial: response rates to matrix-induced autologous chondrocyte implant (MACI) versus microfracture (MFX) by lesion characteristics. Orthop J Sports Med. 2013. https://doi.org/10.1177/2325967113S00029.CrossRefPubMedCentralGoogle Scholar
- 17.Roessing S, et al. The full arthroscopic technique of autologous chondrocyte transplantation using chondrospheres-safety study with 2 years follow up. Cartilage. 2010;1(2 Supplement 1):55S.Google Scholar
- 18.Schreyer T. Comparison in clinical outcome of first generation ACT with ACT of third generation with spheroids. Cartilage. 2010;1(2 Supplement 1):58S.Google Scholar
- 25.Department of Health. NHS reference costs 2012 to 2013. 2013. https://www.gov.uk/government/publications/nhs-reference-costs-2012-to-2013. Accessed 20 Sept 2017.
- 26.National Institute for Health and Care Excellence. Autologous chondrocyte implantation using Chondrosphere for treating symptomatic articular cartilage defects of the knee. 2018. https://www.nice.org.uk/guidance/ta508/resources/autologous-chondrocyte-implantation-using-chondrosphere-for-treating-symptomatic-articular-cartilage-defects-of-the-knee-pdf-82606726260421.