We appreciate the correspondence of Ms. Budri, et al, and Dr. Gooding, et al, and the opportunity to address the common questions they raise regarding the interpretation of adverse event reports derived from spontaneous (also called passive) reporting systems.

Budri, et al, suggest that the active nature of the Cartilage Repair Registry (CRR) would minimize underreporting. In a qualitative sense, this seems a reasonable assertion; however, the quantitative importance of the CRR depends at least in part on the numbers of patients enrolled (as a proportion of all Carticel-treated patients) as well as the duration and completeness of their follow up--data that Budri, et al, did not provide. Provision of these data would allow better estimation of the significance of the underreporting that we acknowledged to be inherent in our study design and that Budri, et al, downplay. Given the lack of such data, we refrained from comparing infectious complication rates following Carticel treatment to other procedures, and we wonder on what quantitative basis Budri, et al, make such comparisons. They also note that our finding about total knee replacement as an adverse event following Carticel treatment was not novel, since a report of this had preceded our paper; however, that report was published subsequent to the submission of our paper to JBJS. This underscores the fact that knowledge of product safety evolves over time and that we should be vigilant, particularly with novel products.

Drs. Gooding and Bentley focus on absence of clear patient selection criteria and post operative rehabilitation protocols in our study. Post-licensure studies of spontaneous reports are not clinical trials. And indeed one of the strengths of studies such as ours is that they evaluate the safety of products in real world use where there is frequently quite heterogeneous practice with regard to patients treated and protocols used. In the face of such heterogeneity, and in some cases as a result of it, passive surveillance systems have made major contributions to the identification of major safety issues of public health importance that necessitated action(1).

1. Strom BL, ed. Pharmacoepidemiology. 4th ed. Sussex, England. John Wylie & Sons; 2005.

To The Editor:

We read with interest the article by Wood, et al,(1) entitled ‘Autologous cultured chondrocytes: Adverse events reported to The United States Food and Drug Administration’. Whilst the authors did allude to some of the limitations of passive reporting systems, we felt that they warrant further emphasis.

In the paper, it is not clear what the pre-transplantation selection criteria for the patients were. At present, the majority of centres use the technique for isolated osteochondral defects and consider any evidence of degenerative changes in the joint as a contra-indication. Also, to prevent recurrent chondral injury, a careful evaluation for pre-disposing factors or concomitant injuries must be undertaken. Minas and Nehrer(2) reported in their review that any tibio femoral malalignment, ligamentous instability, or bone insuffiency must be corrected prior to, or at the time of, cartilage repair. For example, rupture or laxity of the anterior cruciate ligament may result in abnormal translation and rotation of the femur on the tibia and shearing of the chondrocyte graft. Thus, proper patient selection is crucial to the success of this procedure and it is not a ‘one size fits all’ technique.

It would also be interesting to know the post operative rehabilitation protocols for these patients. At our centre, patients are immobilized for 10 days in a cylinder cast but are encouraged to fully weight bear. (The cast prevents shearing forces across the graft by preventing knee flexion and full weight bearing is thought to encourage the redifferentiation of the cultured chondrocytes).

Clearly, the demographics of the patients are important to know,as well as the duration of symptoms, and whether they had previous surgery to try to correct the osteochondral defects prior to transplantation.

It is important to be cautious when interpreting the results of any new surgical technique and the idea of a passive reporting system to pick up adverse events is a good one. However, without the knowledge of how patients were selected and how they were rehabilitated, we feel such a system is of limited value.

References:

1. Wood, J. J., Malek, M. A., Frassica, F. J., Polder, J. A., Mohan, A. K., Bloom, E. T., Braun, M. M., and Cote, T. R.: Autologous cultured chondrocytes: adverse events reported to the United States Food and Drug Administration. J. Bone Joint Surg. Am. 88:503-507, 2006.

2. Minas, T. and Nehrer, S.: Current Concepts in the Treatment of Articular Cartilage Defects. Orthopaedics. 20:525-538, 1997.

To The Editor:

In their recent report, Wood, et al summarize data submitted largely by Genzyme to the FDA’s Adverse Event Reporting System (AERS) from 1996-2003, and conclude that passive safety surveillance has utility for somatic cell therapy. We wish to provide additional information about Carticel adverse event data collection and follow-up,the spectrum of patients receiving Carticel,and Carticel manufacturing that we believe will enrich the context from which the authors’ conclusions were made.

An active reporting system captured adverse event data for Carticel in the Cartilage Repair Registry (CRR), which was established in March 1995 to prospectively gather outcomes data following implantation with Carticel and other cartilage repair therapies [1]. Candidates for Carticel were recruited to enroll in CRR at cartilage biopsy. Safety and efficacy outcomes were collected at autologous chondrocyte implantation (ACI), at 6 months, one year and annually thereafter. This intensive surveillance system captured data that are the basis for the majority of the adverse events reported to the FDA from 1996-2003, and also for several published reports [2-4]. Such data are actively elicited, and are less likely to underestimate the number of adverse events than data derived exclusively from drug and biological product passive reporting systems.

Candidates for ACI include patients with large and/or multiple chondral defects and a history of failed cartilage repair procedures who have severe symptoms and limited function. Although Wood, et al, describe eight patients with total knee replacement (TKR) post-ACI as a novel finding, Minas, et al, previously reported similar data when ACI was used as a joint-preserving alternative to arthroplasty in young patients (mean age 36.9 years) with complex knee pathology [5].

Wood, et al, reported eleven joint infections after ACI, a frequency consistent with infection rates within the range for traditional, terminally sterilized, inert orthopedic implants [6-12]. Carticel has a unique manufacturing process for live cells, which cannot be terminally sterilized. The sterility controls and microbial surveillance systems [5] have proven effective in producing a safe product.

We believe that Carticel data in the AERS are the result of active surveillance that effectively captures adverse event data for a somatic cellular therapy. To date, there are no novel safety concerns for Carticel and the types of adverse event data remain comparable over time [1].

References:

1. Carticel product label, Jan 2006

2. Micheli LJ, Browne JE, Erggelet C, et al. Autologous Chondrocyte Implantation of the Knee : Multicenter Experience and Minimum 3-year Follow-up. Clin J Sport Medicine, 2001 ; 11 : 223-228

3. Browne JE, Anderson AF, Arciero R, et al. Clinical Outcome of Autologous Chondrocyte Implantation at 5 Years in US Subjects. Clin Orthop and Rel Res 2005; N. 436, 237-245

4. Fu FH, Zurakowski D, Browne JE, et al. Autologous Chondrocyte Implantation Versus Debridement for Treatment of Full-Thickness Chondral Defects of the Knee. An Observational Cohort Study with 3-Year Follow-Up. AJSM 2005; Vol. 33, No. 11

5. Minas T, Bryant T. The Role of Autologous Chondrocyte Implantation in the Patellofemoral Joint, Clin Orthop and Rel Res 2005; No. 436, 30-39

6. Kielpinski G, Prinzi S, Duguid J, et al. Roadmap to approval: use of an automated sterility test method as a lot release test for Carticel®, autologous cu1ltured chondrocytes. Cytotherapy 2005; Vol. 7. No. 6, 531- 541

7. Salvati EA, Robinson RP, Zeno SM, et al. Infection rates after 3175 total hip and total knee replacement performed with and without horizontal unidirectional filter air-flow system. J Bone Joint Surg (Am) 1982; 64:525-535.

8. Poss R, Thornhill TS, Ewald FC, et al. Factors influencing the incidience and outcome of infection following total joint arthroplasty. Clin Orthop 1984; 182:117-126.

9. Grogan TJ, Dorey F, Rollins J, Amstutz HC. Deep sepsis following total knee arthroplasty. J Bone Joint Surg (Am) 1986;68:226-234.

10. Johnson DP, Bannister GC. The outcome of infected arthroplasty of the knee, J Bone Joint Surg (Br) 1986;68:289-291.

11. Bengtson S, Knutson K. The infected knee arthroplasty; a 6 year follow-up of 357 cases. Acta Orthop Scand 1991;62:301-11.

12. Blom AW, Brown J,Taylor AH, et al.. Infection after total knee arthroplasty. J Bone Joint Surg (Br) 2004 ;86 :688-691.