MACI: Package Insert and Label Information (Page 2 of 3)

6.2 Postmarketing Experience

Graft complication (e.g., abnormalities to the repair graft that become symptomatic; this could include graft overgrowth [tissue hypertrophy], under-fill or damage to the repair tissue that has elicited a painful response, or mechanical symptoms), graft delamination (i.e., a dislodging of the repair graft from the underlying subchondral bone that has become symptomatic; this can be measured as marginal, partial, or a complete delaminated graft), and tendonitis have been reported during use of MACI outside the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to MACI exposure.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

MACI implantation requires invasive surgical procedures; therefore use during pregnancy is not recommended. Limited clinical data on patients exposed to MACI during pregnancy are available. There are insufficient data with MACI use in pregnant women to inform a product-associated risk. Animal reproduction studies have not been conducted with MACI. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary

There is no information regarding the presence of MACI in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MACI and any potential adverse effects on the breastfed infant from MACI or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of MACI in pediatric patients have not been established.

8.5 Geriatric Use

The safety and effectiveness of MACI in patients over 65 years of age have not been established. Clinical trials of MACI did not include subjects over the age of 55.

11 DESCRIPTION

MACI, autologous cultured chondrocytes on porcine collagen membrane, is a cellular sheet that consists of autologous chondrocytes seeded on a 3 x 5 cm, resorbable porcine Type I/III collagen membrane, for implantation into cartilage defects of the knee. The active ingredients of MACI are the autologous cultured chondrocytes and porcine Type I/III collagen. The autologous chondrocytes are propagated in cell culture and are seeded on the collagen at a density of 500,000 to 1,000,000 cells per cm2. The final MACI implant contains at least 500,000 cells per cm2 and does not contain any preservative.

The product manufacture also uses reagents derived from animal materials. The resorbable, Type I/III, collagen membrane, which is a component of MACI, is porcine-derived. Fetal bovine serum is a component in the culture medium used to propagate the autologous chondrocytes; therefore, trace quantities of bovine-derived proteins may be present in MACI. These animal-derived reagents are tested for viruses, retroviruses, bacteria, fungi, yeast, and mycoplasma before use.

MACI may contain residual gentamicin because it is included during manufacture. Gentamicin is not included in the transport medium used to maintain product stability. Studies determined an average of 9.2 μg residual gentamicin per MACI implant.

A final sterility test is initiated prior to shipping, but the result will not be available prior to implantation. Passing results from preliminary in-process microbial tests are required for release of MACI for shipping.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

No clinical pharmacology studies have been conducted with MACI and a mechanism of action has not been established.

12.3 Pharmacokinetics

Clinical pharmacokinetic studies have not been performed with MACI. Studies in rabbits and horses indicated that the membrane is resorbed over a period of at least 6 months following implantation.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies to evaluate the carcinogenicity or impairment of fertility potential of MACI have not been performed. In vitro studies have shown that the expansion process for chondrocytes does not induce changes to the cellular karyotype.

Four studies (in vitro and in vivo) were conducted to assess the genotoxic potential of the collagen membrane. The results from these studies demonstrated that the collagen membrane was non-mutagenic.

13.2 Animal Toxicology and/or Pharmacology

Implantation of analogous products in critical-size defects in the hind limbs of rabbits and horses did not reveal any serious safety concerns. The products consisted of the same membrane as MACI with rabbit or horse cells, respectively. Non-clinical testing has shown that the collagen membrane is not toxic and is compatible with biological tissue.

14 CLINICAL STUDIES

The effectiveness of MACI implant was evaluated in a 2-year prospective, multicenter, randomized, open-label, parallel-group study, SUMMIT (Superiority of MACI implant versus Microfracture Treatment in patients with symptomatic articular cartilage defects in the knee),1 which enrolled a total of 144 subjects, ages 18 to 54 years, with at least one symptomatic Outerbridge Grade III or IV focal cartilage defect on the medial femoral condyle, lateral femoral condyle, and/or the trochlea. Failure of a prior cartilage surgery was not required for study entry. The subjects were randomized to receive either a 1-time treatment with MACI or microfracture. The co-primary efficacy endpoint was change from baseline to Week 104 for the subject’s Knee injury and Osteoarthritis Outcome Score (KOOS) in two subscales: Pain and Function (Sports and Recreational Activities [SRA])2. Safety also was evaluated through Week 104 [see Adverse Reactions (6.1)].

Of the 72 subjects randomized to MACI, 70 completed the study and 2 discontinued prematurely (1 due to an adverse event [AE] and 1 wished to withdraw). Of the 72 subjects randomized to microfracture, 67 completed the study and 5 discontinued prematurely (1 due to an AE, 1 wished to withdraw, and 3 due to lack of clinical benefit).

At Week 104, KOOS pain and function (SRA) had improved from baseline in both treatment groups, but the improvement was statistically significantly (p = 0.001) greater in the MACI group compared with the microfracture group (Table 3).

Table 3. Change in KOOS Pain and Function (SRA) Scores in the 2-Year Study
LS = least squares; KOOS = Knee injury and Osteoarthritis Outcome Score; SD = standard deviation; SRA = Sports and Recreational Activities. * Difference in least squares mean values at Week 104 [MACI – Microfracture]. ** p-value for difference in co-primary endpoints assessed jointly at Week 104 based on multivariate analysis of variance.
MACI Mean (SD) Microfracture Mean (SD)
N Pain Function N Pain Function
Baseline 72 37.0 (13.5) 14.9 (14.7) 71 35.4 (12.1) 12.6 (16.7)
Week 104 72 82.4 (16.2) 60.9 (27.8) 70 70.9 (24.2) 48.7 (30.3)
Change From Baseline to Week 104 72 45.4 (21.1) 46.0 (28.4) 69 35.2 (23.9) 35.8 (31.6)
LS Means (Week 104) 44.1 46.1 32.4 34.6
Difference * [MACI – Microfracture] 11.8 11.4
p-value ** 0.001

In a responder analysis, the proportion of subjects with at least a 10-point improvement in both KOOS pain and function (SRA) was greater in the MACI group (63/72=87.5%; 95% CI [77.6%, 94.1%]) compared with the microfracture group (49/72=68.1%; 95% CI [56.0%, 78.6%]).

All subjects from the 2-year study had the option to enroll in a 3 year follow-up study (extension study), in which 128 subjects participated. All 65 subjects (100%, 65/65) in the MACI group and 59 subjects (93.7%, 59/63) in the microfracture group completed the extension study. The mean 2-year KOOS pain and function scores remained stable for the additional 3-year period in both treatment groups (Table 4).

Table 4. KOOS Pain and Function (SRA) Scores in the 3-Year Extension Study
Visit MACI Microfracture
N Pain mean (SD) Function mean (SD) N Pain mean (SD) Function mean (SD)
Baseline 65/65 37.1 (13.1) 15.4 (14.8) 63/63 35.2 (12.3) 11.9 (16.2)
2 Years 63/63 82.2 (15.8) 60.5 (26.5) 60/60 71.8 (23.9) 48.9 (30.6)
5 Years 65/64 82.2 (20.1) 61.9 (30.9) 59/59 74.8 (21.7) 50.3 (32.3)

15 REFERENCES

  1. Saris D, Price A, Widuchowski W, Bertrand-Marchand M, Caron J, Drogset JO, et al. Matrix-applied characterized autologous cultured chondrocytes versus microfracture: two-year follow-up of a prospective randomized trial. Am J Sports Med. 2014 Jun;42(6):1384-94.
  2. Roos EM, Lohmander LS. The Knee injury and Osteoarthritis Outcome Score (KOOS): from joint injury to osteoarthritis. Health Qual Life Outcomes. 2003;1:64.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

  • A single patient order may contain 1 or 2 implants, each in its own bottle and shipper, depending on lesion size and number of lesions.
  • MACI, NDC69866-1030-3, contains 1 implant supplied ready for use as a single cellular sheet approximately 3 x 5 cm, in a sterile, sealed, translucent perfluoroalkoxy (PFA) resin bottle and cap. Each bottle contains one 3 x 5 cm implant with a 0.5-cm2 section removed from the lower left-hand corner.
  • MACI, NDC69866-1030-6, contains 2 implants supplied ready for use as cellular sheets approximately 3 x 5 cm, in a sterile, sealed, translucent perfluoroalkoxy (PFA) resin bottle and cap. Each bottle contains one 3 x 5 cm implant with a 0.5 cm2 section removed from the lower left-hand corner.
  • Each bottle is individually sealed in a clear self-seal pouch. Each self-seal pouch is placed into a 95kPa outer bag with absorbent material. These bags are enclosed in an outer carton insulated with ambient temperature gel packs.

Storage and Handling

  • Store MACI at room temperature in its original packaging (outer carton) until ready to use.
  • DO NOT REFRIGERATE or FREEZE, or sterilize MACI.
  • DO NOT USE if the bottle is damaged, has been compromised, or has leaked.
  • Use MACI prior to 11:59 PM ET on the date of expiration printed on the package.
  • Dispose of unused MACI or waste material as surgical biohazardous waste in accordance with local requirements.

17 PATIENT COUNSELING INFORMATION

  • Advise the patient that:
    A cartilage biopsy is needed to manufacture MACI. The biopsy is typically performed as an arthroscopic procedure at the time of diagnosis confirmation.
    The length of time between the biopsy and the implantation of MACI may vary depending on many factors, including the quality and number of cells obtained from the biopsy. On average this will take 6 weeks; however, cells can be held in storage until a convenient date for surgery is agreed upon between the patient and the surgeon.
    Even if the surgeon has taken a biopsy needed to produce MACI, it may be possible that the patient cannot be treated with MACI, (e.g., in case the biopsy is of insufficient quality to produce MACI, if the cells cannot be grown in the laboratory, or if the expanded cells do not meet all the quality requirements).
  • Advise the patient on the risk of graft complications, subsequent surgical procedures, and treatment failure. [See Adverse Reactions (6)]
  • Advise the patient on general complications related to knee surgery, which may include deep vein thrombosis and pulmonary embolism.
  • Advise the patient to closely follow the physician-prescribed rehabilitation program, which will include limitations and allowances for beginning specific physical activities. [See Dosage and Administration (2.3)]

Manufactured by: Vericel Corporation, 64 Sidney Street, Cambridge, MA 02139

MACI® is a registered trademark of Vericel Corporation.

Patents: www.vcel.com/research-and-development

© 2021 Vericel Corporation.

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