0
Scientific Articles   |    
Autologous Cultured Chondrocytes: Adverse Events Reported to the United States Food and Drug Administration
Jennifer J. Wood, PhD, MPH1; Mark A. Malek, MD, MPH2; Frank J. Frassica, MD5; Jacquelyn A. Polder, BSN, MPH2; Aparna K. Mohan, MD, PhD3; Eda T. Bloom, PhD4; M. Miles Braun, MD, MPH4; Timothy R. Coté, MD, MPH2
1 11631 S.W. 2nd Street, Pembroke Pines, FL 33025
2 Centers for Disease Control, MS-A34 (M.A.M.), MS-E08 (J.A.P.), and MS-G25 (T.R.C.), Atlanta GA 30329-4018
5 Johns Hopkins University, 601 North Caroline Street, Baltimore, MD 21287
3 2045 Silverwood Drive, Newtown, PA 18940
4 Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852. E-mail address for M.M. Braun: braunm@cber.fda.gov
View Disclosures and Other Information
Note: The authors thank Dr. Susan Leibenhaut for her contribution in the critical revision of the manuscript.
The authors did not receive grants or outside funding in support of their research for or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
Investigation performed at the Center for Biologics Evaluations and Research, Food and Drug Administration, Rockville, Maryland

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2006 Mar 01;88(3):503-507. doi: 10.2106/JBJS.E.00103
5 Recommendations (Recommend) | 3 Comments | Saved by 3 Users Save Case

Abstract

Background: Carticel is an autologous cultured chondrocyte product that has been approved by the United States Food and Drug Administration for the repair of symptomatic cartilaginous defects of the femoral condyle that are caused by acute or repetitive trauma in patients who have been previously managed with arthroscopy or other surgical procedures. The present report describes the adverse events following Carticel implantation as reported to the Food and Drug Administration from 1996 to 2003.

Methods: We reviewed adverse event reports that had been submitted to the Food and Drug Administration's MedWatch system for information on demographic characteristics, adverse events, and surgical revisions. Adverse events were categorized into sixteen non-mutually exclusive groups. Five categories were used to classify reoperations. Food and Drug Administration regulations require manufacturers to report adverse events; however, reporting by clinicians and others is voluntary. Therefore, adverse event reporting is likely to underestimate the number of event occurrences. Adverse events may be either causally or coincidentally related to the product.

Results: A total of 497 adverse events among 294 patients receiving Carticel were reported. The median interval from Carticel implantation to the diagnosis of an adverse event was 240 days (range, one to 2105 days). The median age of the patients was thirty-eight years, and 63% of the patients were male. Of the 270 events for which the anatomic site was noted, 258 (96%) involved the femoral condyles. More than one adverse event was reported for 135 patients (46%). The most commonly reported events were graft failure (seventy-three patients; 25%), delamination (sixty-five patients; 22%), and tissue hypertrophy (fifty-two patients; 18%). In addition, eighteen surgical site infections were reported, including eleven joint and seven soft-tissue infections. Surgical revision subsequent to Carticel implantation was mentioned in the records for 273 patients (93%). The reasons for the 389 revision procedures included graft-related problems (187 procedures; 48.1%), periarticular soft-tissue problems (ninety-seven procedures; 24.9%), and intra-articular problems (sixty-three procedures; 16.2%). Eight patients had a total knee replacement. Based on the manufacturer's reported distribution of 7500 Carticel lots between 1995 and 2002, 285 patients (3.8%) had an adverse event that was reported to the Food and Drug Administration.

Conclusions: The most common adverse events reported in association with the Carticel technique involved graft failure, delamination, and tissue hypertrophy.

Level of Evidence: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.

Figures in this Article
    Sign In to Your Personal ProfileSign In To Access Full Content
    Not a Subscriber?
    Get online access for 30 days for $35
    New to JBJS?
    Sign up for a full subscription to both the print and online editions
    Register for a FREE limited account to get full access to all CME activities, to comment on public articles, or to sign up for alerts.
    Register for a FREE limited account to get full access to all CME activities
    Have a subscription to the print edition?
    Current subscribers to The Journal of Bone & Joint Surgery in either the print or quarterly DVD formats receive free online access to JBJS.org.
    Forgot your password?
    Enter your username and email address. We'll send you a reminder to the email address on record.

     
    Forgot your username or need assistance? Please contact customer service at subs@jbjs.org. If your access is provided
    by your institution, please contact you librarian or administrator for username and password information. Institutional
    administrators, to reset your institution's master username or password, please contact subs@jbjs.org

    References

    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
    CME Activities Associated with This Article
    Submit a Comment
    Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
    Comments are moderated and will appear on the site at the discretion of JBJS editorial staff.

    * = Required Field
    (if multiple authors, separate names by comma)
    Example: John Doe





    M. Miles Braun, M.D., MPH
    Posted on May 25, 2006
    Dr. Braun et al respond to Drs. Budri et al and Gooding et al
    Center for Biologics Evaluation and Research, Food & Drug Administration, Rockville, MD 20852

    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.

    Chris R. Gooding, MRCS
    Posted on April 19, 2006
    Autologous Cultured Chondrocytes: Adverse Events Reported To The United States Food And Drug Adminis
    Royal National Orthopaedic Hospital, Stanmore, Middlesex, UNITED KINGDOM

    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.

    Eileen M. Budri, RN, MBA
    Posted on April 07, 2006
    Carticel Adverse Events Reports
    Genzyme Corporation, Boston, MA 02142

    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.

    Related Content
    The Journal of Bone & Joint Surgery
    JBJS Case Connector
    Topic Collections
    Related Audio and Videos
    Clinical Trials
    Readers of This Also Read...
    JBJS Jobs
    04/02/2014
    WY - Memorial Hospital of Sweetwater County
    04/23/2014
    MA - UMass Memorial Medical Center
    03/19/2014
    VA - OrthoVirginia