The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 6 October 2010

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1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 6 October 2010 CHONDROCELECT 10,000 cells/microlitre, implantation suspension B/1, 2 or 3 microtubes with Falcon tube, syringes, catheters and sutures (CIP code: ) Applicant: TIGENIX NV Characterised viable autologous cartilage cells expanded ex vivo expressing specific marker proteins. ATC code: (pending) List I Medicinal product reserved for hospital use, for use only by certain specialists (trained and qualified surgeons). This medicine must be distributed exclusively by healthcare establishments that satisfy the criteria described in the risk management plan (cf. appendix). Date of European Marketing Authorisation (centralised): 5 October 2009 Reason for request: Inclusion on the list of medicines approved for hospital use. Medical, Economic, and Public Health Assessment Division 1/17

2 1. CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Characterised viable autologous cartilage cells expanded ex vivo expressing specific marker proteins. Note: Each vial is packaged to give a concentration of 10,000 cells/microlitre i.e. about 4 million autologous human cartilage cells needed for implantation Background CHONDROCELECT is the first cell therapy medicinal product with a marketing authorisation in Europe; it is indicated in the repair of localised and symptomatic cartilage lesions (International Cartilage Repair Society [ICRS] grade III or IV) of the femoral condyle of the knee in adults Indication Repair of localised and symptomatic cartilage lesion of the femoral condyle of the knee (International Cartilage Repair Society [ICRS] 1 grade III or IV) in adults. Concomitant asymptomatic cartilage lesions (ICRS grade I or II) might be present. Demonstration of efficacy is based on a randomised controlled trial evaluating the efficacy of CHONDROCELECT in patients with lesions between 1 and 5cm² Dosage, conditions of use and methods of administration and methods of administration Dosage - The amount of cells to be administered is dependent on the size (surface in cm²) of the cartilage lesion. Each falcon tube contains an individual treatment dose with a sufficient number of cells, obtained from a biopsy, in order to treat the lesion according to its size. The recommended dose is 0.8 to 1 million cells/cm², corresponding to the use of 80 to 100 microlitres suspension of cartilage/cm² of lesion. - Limited data are available on adult patients older than 50 years. - Safety and efficacy in children and adolescents (aged less than 18) have not been established. CHONDROCELECT is therefore not recommended for use in children and adolescents below 18 years. 1 Cartilage lesions are ranked by the International Cartilage Repair Society (ICRS) in 4 grades according to their depth (descriptive arthroscopic analysis): - grade I nearly normal : chondral softening or presence of fibrillations (grade Ia); if lacerations or superficial fissures are present (grade Ib); - grade II abnormal : loss of substance less than 50% of chondral height; - grade III severely abnormal : lesions of more than 50% of thickness which may reach the subchondral bone. A distinction is made between lesions which leave the calcified layer intact (grade IIIa) or cross it (grade IIIb), those affecting the subchondral layer (grade IIIc) and those rated as deep and destructive (grade IIId); - grade IV: osteochondral lesions (affecting the subchondral bone, affecting the superficial layer and impairing the bone surface). Only symptomatic ICRS III and IV lesions require specific treatment (stimulation of the subchondral bone, multiple osteochondral grafts or grafts of chondrocytes) according to the ICRS. 1. 2/17

3 Conditions of use and methods of administration Conditions of use - CHONDROCELECT must be used only by a trained and qualified surgeon, and it must be used only in a hospital setting. - CHONDROCELECT is intended solely for use in autologous cartilage repair and is administered to patients in an Autologous Chondrocyte Implantation procedure (ACI). It must be used in conjunction with surgical debridement (preparation of the injured zone), physical suture of the lesion (insertion of a biological membrane, preferably a collagenic membrane) and a programme of rehabilitation. - In some cases it can be possible that the source chondrocytes of the patient are not expandable or that the release criteria are not met, due to poor biopsy quality, patient characteristics, or manufacturing failure. Therefore it can occur that CHONDROCELECT cannot be delivered. The surgeon will be informed as early in the process as possible, and should hence select an alternative treatment for the patient concerned. - Concomitant knee problems like early osteoarthritis, osteochondritis dissecans, instability of the knee, cartilage lesions at locations other than the femoral condyle, lesions of the ligaments of the knee or of the meniscus, varus or valgus malalignment (abnormal weight distribution in the knee) and inflammatory joint disease are potential complicating factors. In the pivotal study, patients with these comorbidities of the knee were excluded from treatment. Where possible, concomitant knee problems should be corrected prior to or at the latest at the time of CHONDROCELECT implantation. Methods of administration - Local implantation is to be performed under sterile conditions during arthrotomy and requires both preparation of the site of the cartilage lesion and use of a biological membrane to keep the implanted cells in place. Complete joint haemostasis must be achieved prior to insertion of the membrane and implantation of the cells. In clinical studies with CHONDROCELECT a periosteal flap was used as biological membrane. Scientific publications have shown that the collagen membranes can be used as an alternative to the periosteal flap in ACI procedures. However, CHONDROCELECT has not been evaluated in combination with this type of collagen membrane in clinical studies, although it has been used in patients treated with CHONDROCELECT under compassionate use. The safety data obtained in these patients do not indicate a particular concern, and confirm a lower incidence of hypertrophy as mentioned in the scientific literature comparing the use of collagen membranes and the periosteal flap. - Fibrin glue is routinely used in ACI procedures to seal the outside margins and to improve the water-tightness of the compartment of the biological membrane used to cover the cartilage lesion. Fibrin sealant products differ significantly in their quantitative and qualitative composition. In vitro interaction studies were performed with a commercially available fibrin glue containing aprotinin (a fibrinolysis inhibitor of bovine origin). No interaction studies with any other type of fibrin glue were performed. However, the concomitant use of currently marketed fibrin glue with a synthetic fibrinolysis inhibitor (tranexamic acid) in the pivotal clinical trial did not reveal any safety concern. - Implantation must be followed by an appropriate rehabilitation schedule lasting about one year. Its main objective is to avoid early damage which might lead to implant failure. 3/17

4 2. SIMILAR MEDICINAL PRODUCTS 2.1. ATC classification Being obtained Medicine in the same pharmacotherapeutic category or with a similar therapeutic aim None Treatments with a similar therapeutic aim Surgical techniques that can be used to treat cartilage lesions include conservative or palliative surgery, repair surgery, reconstructive surgery and prosthetic surgery: Type of surgery Objective Procedures Conservative or palliative surgery Repair surgery Reconstructive surgery Prosthetic surgery Elimination of microscopic debris Formation of fibrocartilage by stimulation of stem cells of subchondral bone marrow Reconstruction of the microarchitecture of the cartilage to restore its biomechanical and physiological functions Replacement of the damaged part of the joint - Arthroscopic lavage - Debridement - Drilling of the subchondral bone - Abrasion - Implantation of membrane or matrix (AMIC) - Microfractures - Mosaic of multiple osteochondral autografts: mosaicplasty - Osteochondral autograft - Autograft of chrondrocytes or autologous implantation of chondrocytes: ACI Unicompartimental knee prosthesis The only techniques subsidized by the national health insurance are cleaning of the knee joint by arthroscopy (NFJC001), cleaning of the knee joint by arthrotomy (NFJA001) and insertion of a knee prosthesis (NFKA006: Replacement of the knee joint with a unicompartimental femorotibial or femoropatellar prosthesis; NFKA009: Replacement of the knee joint with a fixed-hinge or rotatory prosthesis). The prescription and administration of CHONDROCELECT necessitates the performance of a diagnostic and therapeutic procedure and the use of a medical device (fibrin glue, sutures, or collagen membrane as specified by the SPC for CHONDROCELECT) by a healthcare professional. The procedure for the in situ administration of CHONDROCELECT is not included in the Common Classification of Medical Procedures) (CCAM). The collagen membrane intended to cover traumatic cartilage lesions that can be used in the in situ administration of CHONDROCELECT is not covered. 4/17

5 3. ANALYSIS OF AVAILABLE DATA The clinical dossier is based on a randomized, open comparative study performed between February 2002 and July 2006 at 12 centres in Europe, study TIG/ACT/01&EXT/2000. A request for marketing authorisation has been made to the FDA Efficacy data from the pivotal study Methods This is a prospective, multicentre, randomised, controlled, single-blind study in which the clinical, histopathological and histomorphometric evaluators did not know which treatment had been given. The study had two phases: - A first comparative phase of 12 months: after two pre-inclusion visits, a date was set for the performance of arthroscopy. On the day of arthroscopy, the patients were randomized to either the ICAC group with CHONDROCELECT (technique of Brittberg et al 2 ) or the microfracture group (technique of Steadman et al 3 ). Patients in the microfracture group were treated using the microfracture technique during arthroscopy, those in the CHONDROCELECT group had chondrocytes collected from them during arthroscopy and were then readmitted to hospital 4 weeks later (27 days + 5 days) for implantation of the chondrocytes. All followed a functional rehabilitation schedule with follow-up evaluations until 12 months after surgery. - From the 12th month, patients could go into an extension (follow-up) phase and be followed up for an additional 48 months (i.e. 60 months after surgery, follow-up phase still ongoing) knowing that patients with failed microfracture treatment could go into this subgroup after undergoing ICAC. The main objective was to establish the efficacy of CHONDROCELECT versus microfractures by demonstrating: - the superiority of the structural repair at 12 months - clinical non-inferiority at 12 and 18 months The secondary objective was to evaluate at each visit the clinical superiority of CHONDROCELECT as regards clinical criteria on the KOOS scale and the treatment failures. The primary endpoint is made up of 2 sub-endpoints: - sum of histomorphometric scores for staining with safranin O and H&E and anti-collagen II antibodies (sum of the 2 ratios) and mean of the global histological evaluation score at 12 months 4, 2 Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 1994;331: Steadman JR, Rodkey WG, Rodrigo JJ. Microfracture: surgical technique and rehabilitation to treat chondral defects. Clin Orthop Relat Res 2001;391:S362-S The quality of the structural cartilage repair (primary endpoint) was assessed using samples of regenerated cartilage taken 12 months after ICAC or the performance of microfractures. After tissue staining with safranin O and H&E and for anti-collagen II antibodies, staining was read using two scales: - the modified O Driscoll score based on tissue morphology, staining of the matrix, the integrity of tissue structure, the number of chondrocytes, formation of the calcified tidemark zone, formation of subchondral bone, the architecture of the cartilage surface, defect filling, lateral and basal cartilage tissue integration and tissue inflammation. This scale also describes the formation of hyaline, fibrocartilaginous cartilage and the absence of cartilage; - the ICRS II scale (defined by the International Cartilage Repair Society) made up of 14 subscales evaluating the phenotype of the chondrocytes, tissue structure, and tissue vascularisation and inflammation. 5/17

6 - variation by comparison with the value on inclusion for the mean global KOOS score 5 at 12 and 18 months. It will be noted that the primary endpoint of the study was changed during the study: at the request of the registration authorities 6, other histological rating scales were used (ICRS II) and in particular a clinical criterion was added in the form of the KOOS - Knee Osteoarthritis Outcome score (test of non-inferiority at 12 months). In fact no long-term correlation has been established between the histological results and any clinical benefit. Although there is no validated aggregate score (each analysis must be made for each subgroup) for this scale, the evaluation in the study covered a global KOOS score and did not take account of results concerning sporting and leisure activities. Calculation of the number of subjects required showed that 112 patients (56 per group) were needed to observe an improvement of 60% in the histological and histomorphometric parameters (MODS score) in patients treated with CHONDROCELECT with a power of 90% and a one-sided risk of 2.5%. Note: The calculation of the number of subjects required thus did not use the histological criteria (ICRS II score) or the clinical criterion used to read the results. Secondary endpoints: - Descriptive analysis of change over time (absolute value and variation by comparison with the value on inclusion) in the global KOOS score - Treatment failure rate (renewed procedure). Several secondary endpoints were evaluated in the course of the study. They included: - histological and radiological criteria (subscores for the different measuring scales used to read the slides, measures using MRI and the ICRS visual histological score) ; - the rate of responder patients 7 at 24, 30 and 36 months; - knee pain evaluated using the visual analogue scale (0 to 100) ; - the percentage treatment failure rate 8 During the 12-month comparative phase, patients had to complete the KOOS questionnaire during the second pre-inclusion visit on day 14 then in the 8th week and in the 3rd, 6th, 9th and 12th month after treatment. During the extension phase of the study, the included patients completed the questionnaire at the visits in the 18th, 24th, 30th, 36th, 48th and 60th months after the microfracture technique or ICAC. Non-inferiority in the clinical score on the global KOOS scale between the 2 groups (difference in intra-group variations) was considered to have been established empirically if the lower limit of the confidence interval was greater than -9%. 5 The KOOS scale is based on a self-completion questionnaire covering five areas, each evaluated using the Likert scale graduated from1 to 5: pain, other symptoms such as joint swelling and stiffness, activities of daily living, sporting and leisure activities and quality of life. 6 CHMP Scientific advice; EME/ / A patient was considered a responder if the increase in the KOOS score was at least 10% and/or there was an increase of at least 10% on 3 of the 4 subdomains on the KOOS scale (except for the sub-domain of sport). Patients were also considered improved if they had a reduction in the pain score evaluated on the VAS scale of at least 20% and/or an improvement in the severity of the knee condition in at least one category. A patient was considered a nonresponder if the reduction in the KOOS score was at least 10% and/or there was an reduction of at least 10% on 3 of the 4 subdomains of the KOOS scale (except for the sub-domain of sport). Patients were also considered nonresponders if they had an increase in the pain score evaluated on the VAS scale of at least 20% and/or an increase in the severity of the knee condition in at least one category. A patient was considered not clinically a responder if the scores were between the 2 limits 8 defined as the decision by the surgeon to carry out a new operation on the same lesion and in patients with persistence or recurrence of symptoms 6/17

7 Inclusion and non-inclusion criteria To be included, patients had to be between 18 and 50 years of age and have a single symptomatic localized cartilage lesion of 1 to 5 cm² of the femoral condyle. Patients with a femoropatellar lesion, osteochondritis dissecans, lesions of a depth greater than 0.5 cm and those who had had a meniscal transplant or microfracture or mosaicplasty repair in the last 12 months could not be included. Results: The results at 12 months were published in , those for the extension phase at 36 months (TIG/ACT/001/2000EXT) in The safety data are from the pivotal study and from compassionate use of CHONDROCELECT. Description of the population evaluated Out of 112 patients analysed (out of 118 randomised), 51 were treated with an implant of characterised autologous chondrocytes (ICAC) with CHONDROCELECT + periosteal flap and 61 by the microfracture technique. Randomisation allowed a balanced distribution to be made by age (mean age 33.9 years), sex (61% and 67% of men respectively) and weight (mean weight 78.1 kg and 80.6 kg respectively). Patients had a symptomatic localised cartilage lesion of 1 to 5 cm 2 of the femoral condyle. Patients were naive to all treatment or had already undergone a repair procedure (arthroscopy or other repair technique). During arthroscopy, patients in the ICAC group had up to three samples of cartilage (7 to 8 mm long and several mm wide) taken from the medial femoral condyle outside the load zone demarcated by the 4 mm Wiberg rasp atorium; 77% of the patients had a medial lesion and 23% a lesion of the lateral condyle. The cartilage lesions were grade III or IV (ICRS) in 111 patients; 30% of patients in the ICAC group and 25% of those in the microfracture group had other cartilage lesions. The two groups are not comparable as regards three prognostic criteria: - there were fewer patients with a BMI of > 30 in the CHONDROCELECT group (5.3%) than in the control group (9.8%); - there were more patients who had already undergone knee surgery in the CHONDROCELECT group (88%) than in the microfracture group (77%); - the mean time since the start of symptoms (or knee lesions?) was longer in the CHONDROCELECT group (2 years) than in the microfracture group (1.6 years). Efficacy results: there are usable data for 51 patients (89%) at 12 months and 40 patients (70%) at 18 months in the ICAC group and for all patients at 12 months and 47 (77%) at 18 months in the microfracture group. The extent of the results after 12 months is difficult because they are from small populations. Main efficacy criteria: - The structural repair of the knee cartilage on the basis of histological examinations of the biopsy from the repaired area after 12 months was considered of better quality in the ICAC group (with CHONDROCELECT + periosteal flap) than in the microfracture group: Saris D.B. et al. Characterized chondrocyte implantation results in better structural repair when treating symptomatic cartilage defects of the knee in a randomized controlled trial versus microfracture. Am. J. Sports Med. 2008;36(2): Saris D.B. 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-19S. 7/17

8 The superiority of CHONDROCELECT compared to microfractures is established on the basis of the variation between groups in the mean sums of the ratios of staining with safranin O and H&E and anti-collagen II antibody at 12 months with: = % CI [0.09; 0.44], p = Table Mean of the sums of ratios for staining with safranin O and H&E and anti-collagen II antibody at 12 months for each of the groups (FAS population) CHONDROCELECT* n = 51 Microfractures n = 61 n Mean of the sums of ratios at 12 months (SD) 0.93 (0.41) 0.67 (0.47) Adjusted mean (CE) 1.01 (0.08) 0.75 (0.08) Mean variation between groups (95% CI) 0.27 (0.09; 0.44) * a à ANCOVA model adjusted for age, associated lesions and location of the lesions * p = As regards the clinical evaluation of the results, the analysis of the mean variation in the global KOOS score (0-100) by comparison with the value on inclusion for the mean of the results at 12 and 18 months is shown below. The lower limit of the 95% confidence interval did not exceed -9% [ =1.81 (-3.28, 6.90)], the non-inferiority of ICAC with CHONDROCELECT and periosteal flap, as defined in the study, is established by comparison with the microfracture technique on the global KOOS scale. Table Mean variation in the global KOOS score for the mean of the results at 12 and 18 months by comparison with the value on inclusion for each of the groups (FAS population) CHONDROCELECT n = 51 Microfractures n = 61 n Mean variation in the global KOOS score by (15.55) (15.10) comparison with the value on inclusion Adjusted mean (CE) (2.42) (2.35) Mean variation between groups (95% CI) Hypothesis of non-inferiority margin: 95% CI [-9%, 1.81 (-3.28, 6.90) a + ] a ANCOVA model adjusted for age, associated lesions and location of the lesions Secondary endpoints: The results for the mean variation between groups in the global score for the histological evaluation ICRS II at 12 months are presented below. The analysis of the second histological endpoint was made using 82 biopsy specimens; 25 biopsies were not evaluated initially on account of insufficient quality, weak staining or poor sections in microtome specimens. In the 82 patients whose biopsies are of good quality with adequate staining, the results favour the CHONDROCELECT group: = % CI [2.93; 23.04], p = Table Mean of global score for the histological evaluation ICRS II at 12 months for each of the groups (FAS population) first analysis (n = 82) CHONDROCELECT (n = 51) Microfractures (n = 61) n Mean of the global histological score at 12 months (23.92) (21.85) (SD) Adjusted mean (CE) (5.34) (4.47) Mean variation between groups (95% CI) (2.93; 23.04) *a a ANCOVA model adjusted for age, associated lesions and location of the lesions * p = /17

9 - No statistical difference was observed in the KOOS measurement criteria between the two groups (but an improvement in each group up to 36 months). - There was no reported difference between the groups regarding the variation in pain evaluated using the visual analogue scale for the mean of the results at 12 and 18 months by comparison with the value on inclusion - There was no reported difference between the groups as regards the variation in the long-term activity rate (24, 30, 36 months) by comparison with the value on inclusion. - The numbers of responder patients on the KOOS scale at 24 and 36 months did not differ statistically between the two groups at 24 months, p = and at 36 months, p = Table - Number of responder patients at 24, 30 and 36 months on the KOOS scale (FAS population) Patient status 24 months 36 months CHONDROCE LECT Microfractures (n = 61) CHONDROCE LECT Microfractures (n = 61) (n = 51) (n = 51) n Worsening 3 (6.7%) 10 (19%) 2 (4.9%) 7 (14%) Absence of clinical change 5 (11%) 9 (17%) 5 (12%) 12 (24%) Responder patient 37 (82%) 33 (63%) 34 (83%) 31 (62%) Same results for the numbers of responder patients on the pain scale. - There is no statistical difference for the number of patients with failed treatment between the microfracture group (n = 7 i.e. 11%) and the CHONDROCELECT group (n = 2, i.e. 3.9%) without the difference being statistically significant. It must however be pointed out that the inefficacy of the treatment was also regarded as a severe adverse event because of hospitalisation for a renewed procedure. As regards these observations, the number of failed treatments was 5 (i.e. 9.8%) in the CHONDROCELECT group and 9 (i.e. 15%) in the microfracture group without the difference being statistically significant. The treatment failure rate in the microfracture group is in accordance with the literature data. A subgroup analysis suggests an additional clinical benefit in favour of treatment with CHONDROCELECT in patients who are symptomatic for less than 3 years (27 patients in the CHONDROCELECT group and 32 in the microfracture group) on the global KOOS score at 36 months: difference of ± 4.10 in the CHONDROCELECT group and ± 3.77 in the microfracture group, a difference of = % CI [0.01; 17.97], p = in favour of treatment with CHONDROCELECT. For the subgroup symptoms appeared a long time ago, no difference between the groups was observed. Moreover, a renewed procedure was needed within 36 months after the implantation of CHONDROCELECT for 2 of the 51 patients treated, on account of delamination of the implant or after detachment of the periosteum. By comparison, it was needed because of insufficient or inappropriate repair in 7 of the 61 patients treated with microfractures. Patients with cartilage lesions with a surface area of more than 5 cm 2 received treatment on a compassionate basis. Clinical efficacy data for these patients are not available. 9/17

10 3.2. Adverse effects Data from the pivotal study Data are available for 51 patients; implantation of chondrocytes was not possible in 6 patients. In these patients, a periosteal flap was used to secure the implant. Adverse effects were observed in 78% of patients (40/51) over a postoperative follow-up period of 36 months. The most common were: arthralgia (47.1%), cartilage hypertrophy (27.4%), articular crepitus (17.6%) and swelling of the joint (13.7%). Most of the adverse effects reported were expected as they are linked to the surgical procedure on the open knee. The most common effects reported immediately after the procedure were arthralgia, swelling of the joint and fever. These adverse effects, which were generally moderate, faded in the weeks following the operation. Events of specific interest after 36 months follow-up ACI (CHONDROCELECT + periosteal flap) n = 51 patients Microfractures n = 61 patients Knee pain (arthralgia) 24 (47%) (43%) Cartilage hypertrophy 14 (27%) 8 (14%) Joint swelling 11 (22%) 4 (6.6%) Articular crepitus 9 (18%) 4 (6.6%) - Cartilage hypertrophy: this adverse effect may necessitate arthroscopic surgical treatment. Symptomatic hypertrophy of the cartilage was more common in the CHONDROCELECT group (7 patients, 14%) than in the microfracture group (1 patient, 2%), p = It was rated as mild to moderate in both groups. This complication seems to occur during the cartilage regeneration phase. This adverse effect could be reduced through the use of a collagen membrane (cf. data on compassionate use below). - Effusion of articular fluid: this adverse effect, which is expected after arthrotomy, was reported more commonly (and rated as more severe) in patients in the CHONDROCELECT group than in those in the microfracture group. However, none of these events were rated as serious and all were transient. - Articular crepitus: this was reported more commonly in patients in the CHONDROCELECT group than in those in the microfracture group. - Knee pain (arthralgia): of the 14 patients (27%) with a severe adverse event, 7 (14%) had arthralgia. 10/17

11 Data on the use of CHONDROCELECT on a compassionate basis The adverse effects collected from 334 patients included in a compassionate use programme were reported. Comparison after 36 months between safety results from the pivotal study and the compassionate use programme ACI (CHONDROCELECT + periosteal flap) n = 51 patients Compassionate use n = 334 patients Knee pain (arthralgia) 24 (47%) 67 (20%) Symptomatic cartilage hypertrophy 7 (14%) 6 (1.8%) Joint effusion 5 (9.8%) 24 (7.2%) Articular crepitus 9 (18%) 17 (5.1%) Joint swelling 7 (14%) 23 (6.9%) The occurrence of the following events can be recorded: - Cartilage hypertrophy: in most patients, a collagen membrane was used instead of a periosteal flap to cover the lesion. In fact, according to several recent publications, cartilage hypertrophy is associated with use of the periosteal flap (Gooding et al., 2006) and its incidence is reduced by using a collagen membrane rather than a periosteal flap (Haddo et al., 2004; Gooding et al., 2006; Steinwachs and Kreuz, 2007; Niemeyer et al., 2008). This is suggested by a comparison of the incidence of cartilage hypertrophy in patients with a collagen membrane (1.8%) with those in the pivotal study who had a periosteal flap (25%). - Arthrofibrosis : a greater incidence of arthrofibrosis and a reduction in joint looseness were observed more commonly in patients with a patellar lesion (8.2% and 13.1% respectively) than in those with non-patellar lesions (0.6% and 2.6% respectively). As in the pivotal study, arthralgia was the commonest adverse effect (67 out of 334 patients, 20%) Other data: - According to the HAS interim report of February 2005, autologous chondrocyte implantation brought a clinical improvement in up to 2 years follow-up in interim evaluations of 3 clinical studies. Same results in 8 studies with a low level of evidence and follow-up for up to 5 years. The safety data are difficult to assess. The available clinical data were considered encouraging but difficult to interpret. Autologous chondrocyte implantation was regarded as an emerging technique that is currently being evaluated. Autologous chondrocyte implantation introduces a new biotechnology (cell culture) and an unfamiliar surgical technique (fixation of the periosteal flap). It would necessitate standardisation of the technique. 11/17

12 The report concluded that it was not possible to establish the position of autologous chondrocyte implantation among surgical treatments for loss of chondral substance because of a lack of comparative studies and long-term follow-up. Basic and clinical research into this treatment option was to make it possible to refine the characterisation of chondrocytes, define release criteria for chondrocyte culture and for making advances in choosing the best matrix to replace the periosteal flap. - An application for the award of marketing authorisation for CHONDROCELECT is currently being examined by the Food and Drug Administration (FDA): after analysing the methods of the pivotal study in the MA dossier submitted to the European Medicines Agency: EMA), the FDA (15 March 2010) requested that an additional confirmatory study be carried out before the BLA (Biologic License Application) authorisation procedure could be implemented. The European Medicines Agency (EMA) also asked for a post-ma study to be carried out as part of the RMP. - Risk of tumour de-differentiation and proliferation of the implanted chondrocytes CHONDROCELECT is based on autologous chondrogenic cells characterised by expression of specific marker proteins. The company TIGENIX states that this characterisation is based on tests involving the formation of tissue in vivo, production of proteins and proteoglycans needed for the formation of the cartilage matrix, and the cellular expression of genes involved in cartilage and chondrocyte biology. - Preparation of chondrocyte cultures necessitates the construction of a specialised and specific production site for this treatment and specific traceability must be put in place to avoid errors of manufacture, labelling and administration of the medicinal product. Analysis of the results For the performance of clinical studies and according to the HAS report (2005), the inclusion criteria of the studies should take account of the aetiological context, clinical criteria (IKDC score) and anatomical criteria (ICRS classification 2000: surface, situation, depth). The fact that the pivotal study was comparative, randomised and used the ICRS rating system (to describe the lesions) must be seen as a positive point (taking account of the pre-existing data). The choice of the microfracture technique as comparator is also acceptable. When patients aged 15 to years with symptomatic, unipolar traumatic loss of chondral substance (subjective IKDC or ICRS score < 55) preferentially of the femoral condyle after nonsurgical management, autologous chondrocyte implantation should be compared with the microfracture technique for lesions between 1 and 3 cm 2 in size according to HAS (2005). On the other hand, HAS advised comparing osteochondral implantation (mosaicplasty) for lesions of between 3 and 8 cm 2. Moreover, since none of the possible surgical techniques has demonstrated its superiority by comparison with the others in preventing gonarthrosis in particular, a control group with nonsurgical management could have been considered 11, Magnussen R.A et al. Treatment of focal articular cartilage defects in the knee. A systematic review. Clin Orthop Relat Res 2008;466: Wasiak J, Clar C, Villanueva E. Autologous cartilage implantation for full thickness articular cartilage defects of the knee (review). The Cochrane Collaboration. Issue 1, /17

13 Reading the results prompts several remarks: Clinical relevance of the results - The main objective of study TIG/ACT/001/2000 was to demonstrate the superiority of CHONDROCELECT in structural repair at 12 months by comparison with the microfracture technique. However, an evaluation after just 12 months seems premature as an assessment of the absence of de-differentiation of the implanted chondrocytes. The clinical impact of the histological results is hypothetical. - The CHMP experts advised the use of a clinical superiority criterion (because of the complex nature of the ACI technique by comparison with the microfracture technique and the paucity of available data on the efficacy of microfractures in preventing osteoarthritis). The company therefore added the global KOOS score as primary clinical endpoint in its study. Only non-inferiority on the global KOOS score has been established. Moreover, the size of the effect seems to be small (expert opinion). - At 12 and 18 months, the two procedures seem to give clinical scores of the same order of magnitude in favour of the two procedures. The results of the subgroup analysis with symptoms present for less than 3 years, in favour of the ICAC procedure (with CHONDROCELECT and periosteal flap) are merely exploratory in nature; they must be confirmed in the longer term. The non-inferiority results at 12 and 18 months are debatable given the methods used to obtain them. We are unaware of any long-term results for the two techniques (as the EPAR states). Data on functional disturbance and improvements in symptoms and function for the patient are needed. Trends in the use of analgesics are not documented. The transferability of the results is not assured: - The size of the populations is limited. - The surgical teams received intensive training in the techniques used in this study. The success of the cartilage repair is partly linked to the quality of the surgical procedure. - There are no observations on the impact of body mass index (BMI) on the progress of the implant but, as the SPC states, bibliographical data show that a BMI of > 30 can harm the success of the technique used with CHONDROCELECT (ICAC). - Problems with the knee such as early osteoarthritis, osteochondritis dissecans, instability of the knee, cartilage lesions at locations other than the femoral condyle, lesions of ligaments of the knee or of the meniscus, varus or valgus malalignment (abnormal weight distribution in the knee) and inflammatory joint disease are potential complicating factors. In the pivotal study with CHONDROCELECT, patients with these comorbidities of the knee were excluded from treatment. The SPC states that where possible, concomitant knee problems should be corrected prior to or at the latest at the time of CHONDROCELECT implantation. Similarly, joint instability (existence of looseness) must be identified where it exists. - Chondrocytes were injected under a periosteal flap taken from the proximal region of the medial tibia. According to the evaluation made by the CHMP and as stated in the SPC, publications have shown that the collagen membranes currently marketed could be used as an alternative to the periosteal flap in ACI techniques. However, CHONDROCELECT was not evaluated in combination with this type of membrane in the pivotal study on which the European MA is based. 13/17

14 The SPC gives reason to believe that the use of CHONDROCELECT with a collagen membrane is conceivable or indeed desirable. However, there is no strong consensus to recommend this practice (cf. evaluation report made by the Austrian agency 13 ) Conclusion The evaluation of the clinical benefit of CHONDROCELECT was based on a 12-month open, randomized comparative clinical study in patients aged 18 to 50 years with a single symptomatic and localised cartilage lesion of an area between 1 and 5 cm² of the femoral condyle. Patients were treated using either the technique with the implantation of characterised autologous chondrocytes (ICAC) with CHONDROCELECT or the microfracture technique. Patients in the microfracture group were treated in a single surgical procedure during initial arthroscopy. Those in the CHONDROCELECT group first had chondrocytes collected from them during arthroscopy and were then readmitted to hospital 4 weeks later for implantation of CHONDROCELECT during arthrotomy, on a periosteal flap (sutured and glued). All patients followed a 12-month functional rehabilitation schedule after surgery. From the 12th month, patients could go into an extension phase and be followed up for an additional 48 months (i.e. 60 months after surgery, follow-up phase still ongoing) knowing that patients with failed treatment after microfractures could receive ICAC and then be followed up in the extension phase. The main objective of this study was to demonstrate, after 12 months, the superiority of ICAC with CHONDROCELECT over the microfracture technique in terms of the quality of the structural repair and to compare the clinical efficacy of the two techniques on the composite KOOS score (Knee Osteoarthritis Outcome) measuring, using a self-completion questionnaire, pain and other symptoms (swelling and stiffness of the joint, activities of everyday living, sporting activities, quality of life). In 112 patients (51 CHONDROCELECT, 61 microfractures), the quality of the structural repair was greater with CHONDROCELECT. This result seems to be confirmed during the follow-up phase. However, its clinical relevance is unknown (no established clinical/histological correlation) and it seems premature to assess the absence of chondrocyte de-differentiation after a period of just 12 months. Only the results of a clinical evaluation would allow conclusions to be drawn as to the relative therapeutic value of the two techniques. At present, only non-inferiority on the KOOS score at 12 months has been tested and the size of the effect is, according to the experts, modest to small. The variation in pain at 12 and 18 months by comparison with the level on inclusion and in the level of activity at 24, 30 and 36 months did not differ between the groups. In patients symptomatic for less than 3 years (a posteriori subgroup analysis), an additional clinical benefit at 36 months in favour of the procedure with CHONDROCELECT is observed but not clearly established. These data are merely exploratory in nature. The available clinical data thus do not yet make it possible to establish, given the current state of the data, the therapeutic value of ICAC with CHONDROCELECT by comparison with microfractures (the technique most often used for small lesions); a possible preventive effect on the occurrence of arthritic lesions has not been established. The safety of the two techniques seems acceptable given that the ICAC technique necessitates arthrotomy and taking a periosteal flap from the tibia. 13 Autologous chondrocyte implantation. Systematic review. Ludwig Boltzmann Institut, heath technology assessment, Vienna, December /17

15 Adverse effects, generally moderate, were observed in 78% of patients with CHONDROCELECT. Some were more common than with microfractures: arthralgia (47% vs 43%), cartilage hypertrophy (27% vs 14%) (the frequency seems to be reduced by using a collagen membrane instead of periosteum), articular crepitus (18% vs 6.6%), joint swelling (22% vs 6.6%). Since the robustness of the results is debatable (a single study, limited population, no demonstration of clinical superiority), a confirmatory study seems essential. The transferability of the results (conditions for use of the technique, size of populations, knee comorbidities excluded, absence of efficacy data with collagen membrane) is not assured. 14 Macmul S et al. Treating articular cartilage injuries of the knee in young people. BMJ 2010 ;340 :c998 doi : /bmj.c Autologous chondrocyte implantation. Systematic review. Ludwig Boltzmann Institut, heath technology assessment, Vienna, December Hulet C et al. Cartilage implants and transfers. Work of the French Orthopaedic Society of the West. Le Havre meeting, June Communications. Revue de chirurgie orthopédique et traumatologique 2009;95S :S60-S66. 15/17

16 4. TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit The joint consists of periarticular and subchondral bone, articular cartilage, synovial membrane, the joint capsule and periarticular muscles. Loss of chondral substance may be the result of injuries and diseases causing irreversible tissue lesions such as degenerative or inflammatory joint diseases and joint instability associated with a ligament or meniscus lesion. Spontaneous scar formation of these lesions is difficult if not impossible, since the capacity of joint cartilage to repair itself is very limited. Cartilage lesions are difficult to diagnose clinically since there is no correlation between clinical symptoms and the state of the cartilage 17. Deep, symptomatic lesions in a weight-bearing area can cause pain in the knee and loss of joint function leading to disability and marked impairment of the quality of life. Cartilage lesions can progress to osteoarthritis, a chronic degenerative joint disease which can be serious and disabling. Early repair of symptomatic cartilage lesions can potentially avoid or delay irreversible changes in the joint surface 18. The implantation autologous of chondrocytes (with CHONDROCELECT implanted on a periosteal flap) is a technique for regeneration of the joint cartilage in the knee. It is intended as symptomatic and possibly preventive treatment. However, its clinical efficacy (size of effect, impact on quality of life, preventive effect on the development of gonarthrosis in particular) has not been established in the clinical dossier as it stands. Public health benefit: Little is known about the prevalence and incidence of osteochondral loss. It has multiple origins and the commonest cause in young subjects is a sports injury. It can lead to impaired quality of life and ultimately to osteoarthritis, particularly when injuries are in load-bearing areas, without that progression being properly documented. The public health burden of these conditions may therefore be rated as small for the subpopulation of patients likely to benefit from autologous chondrocyte implantation, i.e. adult patients with localised and symptomatic grade III and IV lesions. The prevention of osteoarthritis to which CHONDROCELECT could contribute may be a public health need that is an established priority, by helping to reduce the functional impairment and incapacity induced by osteoarthritis and to improve the quality of life of the persons affected (Public Health Law 2004, Plan to improve the quality of life of patients with chronic diseases). However, in the absence of information about the longterm prevention of osteoarthritis, the medicinal product CHONDROCELECT is unlikely to provide an additional response to the identified public health need. Given that the available data are from a single study in a limited number of patients and based on a composite clinical criterion such as the KOOS score, the impact of treatment with CHONDROCELECT on functional impairment and quality of life cannot be established, despite obtaining histological samples of hyaline cartilage. Moreover, quality of life data from questionnaire SF-36 from the study are not available. The transferability of results from the pivotal study to practice is not assured (exclusion criteria particularly in the event of other articular complaints, need for patient compliance with the rehabilitation schedule). 17 Interim report. Evaluation of autologous chondrocyte implantation in the knee joint: ACI, HAS, February EPAR Scientific discussion - ChondroCelect 16/17

17 In addition, carrying out implantation involves at least two hospitalisations (performance of arthroscopy and biopsies in one, then implantation of the cells during arthrotomy in the other) whereas the microfracture technique requires just one hospitalisation. CHONDROCELECT can therefore be expected to have a potentially negative impact on the healthcare system. Consequently, taking account of this information, CHONDROCELECT is not expected to have any public health benefit. Apart from palliative treatments for the elimination of microscopic debris (arthroscopic lavage and debridement), there are several possible treatments: so-called osteochondral stimulation techniques leading to the appearance of fibrocartilage (microfractures, perforation of the subchondral bone after Pridie, abrasion) in the case of fairly small lesions and techniques for cartilage repair by replacement: osteochondral allografts and autologous osteocartilaginous grafts (mosaicplasty) as alternatives to autologous chondrocyte implantation. There is a consensus view that surgical treatment is possible only for symptomatic grade III and IV knee cartilage lesions according to the ICRS arthroscopic classification. According to the group of experts consulted by the HAS in 2005, the main indications for autologous chondrocyte implantation are lesions between 1 and 3 cm 2 in size. None of the current surgical techniques has demonstrated its superiority by comparison with the others. The benefit of surgical techniques by comparison with drug treatment combined with rehabilitation is not known. Although the Committee believes that it is an innovative biotechnology, the actual benefit of CHONDROCELECT must provisionally be regarded as insufficient to justify its reimbursement, given the current state of the data. The Committee is unable to evaluate its actual benefit, particularly in preventing the onset of osteoarthritis in the long term Transparency Committee recommendations The transparency Committee does not recommend inclusion on the list of medicines approved for hospital use. 17/17