Autologous Chondrocyte Implantation with Chondrosphere for Treating Articular Cartilage Defects in the Knee: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

  • Xavier Armoiry
  • Ewen Cummins
  • Martin Connock
  • Andrew Metcalfe
  • Pamela Royle
  • Rhona Johnston
  • Jeremy Rodrigues
  • Norman Waugh
  • Hema MistryEmail author
Review Article


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.

Author Contributions

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 ( for further project information: 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. 1.
    International Cartilage Repair Society. ICRS score/grade. 2000. Accessed 25 Jul 2016.
  2. 2.
    National Institute for Health and Care Excellence. Autologous chondrocyte implantation with Chondrosphere for treating articular cartilage defects [ID851]. 2017. Accessed 14 Aug 2017.
  3. 3.
    National Institute for Health and Care Excellence. Knee cartilage defects - autologous chondrocyte implantation [ID686]: in development [GID-TAG446]. 2017. Accessed 15 Aug 2017.
  4. 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. Accessed 15 Oct 2017.
  5. 5.
    Urquhart DM, et al. What is the effect of physical activity on the knee joint? A systematic review. Med Sci Sports Exerc. 2011;43(3):432–42.CrossRefGoogle Scholar
  6. 6.
  7. 7.
    European Medicines Agency. MACI: matrix-applied characterised autologous cultured chondrocytes. 2014. Accessed 25 Jul 2016.
  8. 8.
  9. 9.
    Becher C, et al. Safety of three different product doses in autologous chondrocyte implantation: results of a prospective, randomised, controlled trial. J Orthop Surg Res. 2017;12(1):71.CrossRefGoogle Scholar
  10. 10.
    Niemeyer P, et al. The effect of cell dose on the early magnetic resonance morphological outcomes of autologous cell implantation for articular cartilage defects in the knee: a randomized clinical trial. Am J Sports Med. 2016;44(8):2005–14.CrossRefGoogle Scholar
  11. 11.
    Higgins JP, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. Bmj. 2011;343:d5928.CrossRefGoogle Scholar
  12. 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. Scholar
  13. 13.
    Saris DB, et al. Treatment of symptomatic cartilage defects of the knee: characterized chondrocyte implantation results in better clinical outcome at 36 months in a randomized trial compared to microfracture. Am J Sports Med. 2009;37(Suppl 1):10s–9s.CrossRefGoogle Scholar
  14. 14.
    Vanlauwe J, et al. Five-year outcome of characterized chondrocyte implantation versus microfracture for symptomatic cartilage defects of the knee: early treatment matters. Am J Sports Med. 2011;39(12):2566–74.CrossRefGoogle Scholar
  15. 15.
    Fickert S, et al. One-year clinical and radiological results of a prospective, investigator-initiated trial examining a novel, purely autologous 3-dimensional autologous chondrocyte transplantation product in the knee. Cartilage. 2012;3(1):27–42.CrossRefGoogle Scholar
  16. 16.
    Maiotti M, et al. Transplantation of tissue-engineered cartilage for repair of osteochondral defects in the knee (SS-27). Arthroscopy J Arthrosc Relat Surg. 2012;28(6):e15–6.CrossRefGoogle Scholar
  17. 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. 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
  19. 19.
    Siebold R, et al. Second-look assessment after all-arthroscopic autologous chondrocyte implantation with spheroides at the knee joint. Knee Surg Sports Traumatol Arthrosc Off J ESSKA. 2016;24(5):1678–85.CrossRefGoogle Scholar
  20. 20.
    Mistry H, et al. Autologous chondrocyte implantation in the knee: systematic review and economic evaluation. Health Technol Assess. 2017;21(6):1–294.CrossRefGoogle Scholar
  21. 21.
    Gerlier L, et al. The cost utility of autologous chondrocytes implantation using ChondroCelect (R) in symptomatic knee cartilage lesions in Belgium. Pharmacoeconomics. 2010;28(12):1129–46.CrossRefGoogle Scholar
  22. 22.
    Dong H, Buxton M. Early assessment of the likely cost-effectiveness of a new technology: a Markov model with probabilistic sensitivity analysis of computer-assisted total knee replacement. Int J Technol Assess Health Care. 2006;22(2):191–202.CrossRefGoogle Scholar
  23. 23.
    Jansson KA, Granath F. Health-related quality of life (EQ-5D) before and after orthopedic surgery. Acta Orthop. 2011;82(1):82–9.CrossRefGoogle Scholar
  24. 24.
    Brazier J, Roberts J, Deverill M. The estimation of a preference-based measure of health from the SF-36. J Health Econ. 2002;21(2):271–92.CrossRefGoogle Scholar
  25. 25.
    Department of Health. NHS reference costs 2012 to 2013. 2013. Accessed 20 Sept 2017.
  26. 26.
    National Institute for Health and Care Excellence. Autologous chondrocyte implantation using Chondrosphere for treating symptomatic articular cartilage defects of the knee. 2018.

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Warwick Evidence, Warwick Medical School, University of WarwickCoventryUK
  2. 2.McMDCHarrogateUK
  3. 3.Warwick Clinical Trials Unit, Warwick Medical School, University of WarwickCoventryUK
  4. 4.Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of OxfordOxfordUK

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