Forum: Science & Society
Cartilage repair and replacement in the knee: a regulatory perspective J. Terrig Thomas1, Bruce S. Schneider1, Elizabeth L. Frank2, and Sylva J. Krizan2 1 2
Center for Biologics Evaluation and Research, FDA, Rockville, MD, USA Center for Devices and Radiological Health, FDA, Silver Spring, MD, USA
Background The number of investigational knee cartilage repair or replacement product submissions (hereafter referred to as cartilage products) received by the FDA is increasing. This trend may reflect the rise in cartilage repair publications and active product development (Figure 1). To describe its current thinking on cartilage products, the FDA recently finalized guidance entitled ‘Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage’. This article provides an overview of cartilage product regulation and the Cartilage Guidance document. Regulatory pathway for cartilage products The regulatory pathway for marketing approval of investigational cartilage products in the USA depends on the applicable legal definitions. Depending on its composition, a cartilage product may be defined as a tissue, non-tissue biologic, device, drug, or combination of two or more of these. If classification is unclear, the FDA encourages informal communications with its review staff, and the Office of Combination Products (OCP). In some cases, a formal Request for Designation (RFD) may be submitted to the OCP, whose decision is legally binding [1]. In addition, for human cells, tissues, and cellular and tissue-based products (HCT/Ps), the FDA Tissue Reference Group (TRG) considers questions posed by product developers and makes regulatory pathway recommendations [2]. A more detailed discussion of the regulatory processes relevant to cartilage products is available [3]. Tissues Tissues categorized as HCT/Ps are regulated by the Center for Biologics Evaluation and Research (CBER) under 21 CFR Part 1271 and Section 361 of the Public Health Service Act (PHSA). For regulation solely under Section 361 the following four criteria in Part 1271 must be met. The product: (i) must be minimally manipulated; (ii) must be intended for homologous use only; (iii) must not be combined with another drug or device (with some exceptions); and (iv) must not have a systemic effect, and must not be dependent upon metabolic activity of living cells for Corresponding author: Thomas, J.T. ([email protected]).
its primary function (unless use is either autologous or allogeneic in a first or second degree blood relative). FDA guidance regarding application of the various requirements of Part 1271 (21 CFR 1271) are available [4]. HCT/Ps not meeting all four criteria are regulated as drugs, biologic drugs, or medical devices. Biologic drugs For cartilage products regulated as biologic drugs, an Investigational New Drug (IND) application is necessary for clinical investigation. Prior to marketing, the product must be demonstrated to be safe, pure, potent, and effective, and approval of a Biologics License Application (BLA) is required. Guidance on biologics regulation is available [5]. Medical devices Medical devices reviewed by the Center for Devices and Radiological Health (CDRH) are categorized into three risk-based classes ranging from the lowest (Class I) to the highest (Class III) risk. Cartilage products regulated as devices are classified as Class III, and clinical studies conducted in the USA must be conducted under an Investigational Device Exemption (IDE). Prior to marketing, review and approval of a Pre-Market Approval (PMA) application are required. Guidance on the processes and data expectations for IDEs and PMAs is available [6]. Combination products In most cases, a combination product is ‘a product comprising two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity’ [21 CFR 3.2 (e)1]. A combination product can also be a product packaged separately, but intended for use only when combined with another approved product [21 CFR 3.2(e)2–4]. Assignment of the FDA Center with primary jurisdiction for a combination product typically is based on the primary mode of action through which the product achieves its therapeutic effect [21 CFR 3.4(a)]. If this is uncertain, the OCP designates the Center based on other, secondary factors [21 CFR 3.4(b)] [7]. FDA review approach for cartilage products CDRH/CBER reviewers collaborate to ensure guidance documents, standards, and review practices are consistent. Advice from outside experts is also sought on an ad hoc 665
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Trends in Biotechnology December 2013, Vol. 31, No. 12
Lesion size/location (scaled to the clinical lesion). Appropriate endpoints (clinically relevant). Arthroscopic and/or magnetic resonance imaging (MRI) evaluations.
100 000 Key:
Carlage publicaons Carlage repair publicaons
10 000
The Cartilage Guidance [12] provides recommendations on appropriate animal models, based on the AC meeting discussions [10,11] and on the American Society for Testing and Materials (ASTM) standards on the assessment of devices for cartilage repair [13].
1000
100
10
1 1990–1995
1996–2000
2001–2005
2006–2010
TRENDS in Biotechnology
Figure 1. PubMed search showing the distribution of cartilage publications from 1990 to 2010. The number of publications containing the term ‘cartilage repair’ has increased more than those with the term ‘cartilage’.
basis. The FDA encourages product developers to schedule pre-IND/IDE submission meetings [8,9] to obtain FDA feedback on regulatory issues, product characterization, and the design of nonclinical and clinical studies. The FDA has held two public advisory committee (AC) meetings to discuss issues related to cartilage product regulation. In 2005, the FDA solicited advice on preclinical and clinical assessments of cartilage products [10] and published a draft guidance document. In 2009, at a second AC meeting [11], comments received on the draft guidance were discussed before the FDA published the final Cartilage Guidance [12]. The following provides an overview of this guidance. Product description In brief, for IDEs (see 21 CFR Part 812), information should be provided for the manufacture of the device component in sufficient detail to allow a judgment regarding quality control [21 CFR 812.20(b)] [3]. For INDs (see 21 CFR Part 312), adequate Chemistry, Manufacturing, and Control (CMC) information is required to assure the identity, purity, and stability of the product [21 CFR 312.23(a)] [7]. Please refer to the relevant guidance documents for further information [5,6,12]. Nonclinical data Nonclinical data, as listed below, are necessary to demonstrate an acceptable product safety profile prior to initiating clinical studies. Animal studies Biological response to the final product and/or components (e.g., cells and scaffold). Durability of therapeutic effect (e.g., repair of the lesion). Potential local/systemic adverse effects (e.g., product distribution, degradation, and tumorigenicity). Dose response (e.g., responses to material constituents and cell number). 666
Mechanical testing Where appropriate, major mechanical testing considerations for cartilage devices are: Ability of implant to withstand expected in vivo static and dynamic loading (e.g., compression, shear, and tension). Appropriate analysis of fixation method (e.g., producttissue integration strength). Propensity of implant to generate wear debris. Mechanical testing should include assessment immediately following implantation, throughout the repair process, and at completion of the study. Testing should compare repaired/regenerated tissue to control tissue. Biocompatibility testing Biocompatibility testing may be required to determine any potentially harmful physiological effects of the investigational device. For more information, the International Organization for Standardization (ISO) and ASTM standards provide overviews of the minimum required biocompatibility testing [14,15]. Clinical evaluation Ideally, clinical development of an investigational cartilage product proceeds through a series of exploratory (feasibility or Phases 1 and 2) and confirmatory (pivotal or Phase 3) clinical studies. Exploratory studies are designed to evaluate adverse events, failures, implantation technique, and bioactivity data. Addition of control groups may provide some indication of clinical efficacy, depending on sample size and magnitude of the treatment effect. The results should help design subsequent confirmatory trials by providing support for product design/dosage, surgical technique, eligibility criteria, clinical evaluations, primary endpoints, and long-term follow-up. Confirmatory studies should use a randomized, concurrent-controlled design, in which control subjects receive current standard-of-care [12]. Blinding of investigators, evaluators, and subjects is desirable but may not always be feasible. Primary efficacy endpoints should evaluate both joint pain and function, using appropriate scoring systems [e.g., the Knee Injury and Osteoarthritis Outcome Score (KOOS) and the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form2000] generally from 1 to 3 years following product administration. Confirmatory studies should be designed to demonstrate superiority of the product, in terms of improvements in both pain and function, compared to
Forum: Science & Society the active control. All adverse events, revisions, removals, and reoperations should be recorded to provide an adequate safety database. Subjects should be followed for safety and effectiveness for a minimum of 2 years, preferably longer, with additional follow-up required as part of postmarketing surveillance. Imaging studies are strongly encouraged to provide further information regarding product performance as well as scientific knowledge. At present, imaging studies are used as secondary endpoints, and the protocol should specify the X ray/MRI technique, the views to be taken, and evaluation methodology. Images should be interpreted by at least two independent (blinded) readers. Conceivably, research may yield validated surrogates for clinical outcomes comprising genomic, proteomic, metabolic, or other biomarkers, together with in vivo imaging data. Surrogate validations will depend on correlation with improvements in pain and function; a challenge that could be addressed collaboratively among sponsors and investigators. Please refer to the Cartilage Guidance [12] for more specific recommendations on clinical evaluation of cartilage products. Concluding remarks Basic and clinical research, combined with knowledge of the regulatory process, is critical to bring safe and effective cartilage products to market. The focus of the FDA review and regulatory decision making process is evaluation of the clinical benefit/risk profile for every investigational cartilage product. Product developers should communicate with the FDA early and often, both before (pre-IND/IDE) and following submission of the IND/IDE. Acknowledgments The authors wish to thank members of the CBER/CDRH Cross-Center Working Group and CBER/CDRH senior management for their valuable feedback and internal review of the manuscript.
References 1 U.S. Food and Drug Administration (2011) Guidance for Industry: How to Write a Request for Designation (RFD) (http://www.fda.gov/ downloads/RegulatoryInformation/Guidances/UCM251544.pdf) 2 U.S. Food and Drug Administration (2013) Vaccines, Blood and Biologics, Tissue Reference Group (http://www.fda.gov/ biologicsbloodvaccines/tissuetissueproducts/regulationoftissues/ ucm152857.htm) 3 Lee, M.H. et al. (2010) Considerations for tissue-engineered and regenerative medicine product development prior to clinical trials in the United States. Tissue Eng. B Rev. 16, 41–54
Trends in Biotechnology December 2013, Vol. 31, No. 12 4 U.S. Food and Drug Administration (2012) Vaccines, Blood and Biologics, Tissue Guidances (http://www.fda.gov/BiologicsBlood Vaccines/GuidanceComplianceRegulatoryInformation/Guidances/ Tissue/default.htm) 5 U.S. Food and Drug Administration (2013) Vaccines, Blood and Biologics, Guidance, Compliance, and Regulatory Information (Biologics) (http://www.fda.gov/cber/guidelines.htm) 6 U.S. Food and Drug Administration (2013) Medical Devices, Device Advice: Comprehensive Regulatory Assistance (http://www.fda.gov/ MedicalDevices/DeviceRegulationandGuidance/default.htm) 7 U.S. Food and Drug Administration (2006) Guidance for Industry and FDA Staff: Early Development Considerations for Innovative Combination Products (http://www.fda.gov/downloads/Regulatory Information/Guidances/ucm126054.pdf) 8 U.S. Food and Drug Administration (2012) Vaccines, Blood and Biologics, OCTGT Learn (http://www.fda.gov/BiologicsBloodVaccines/ NewsEvents/ucm232821.htm) 9 U.S. Food and Drug Administration (2012) Draft Guidance for Industry and FDA Staff Medical Devices: The Pre-Submission Program and Meetings with FDA Staff (http://www.fda.gov/downloads/Medical Devices/DeviceRegulationandGuidance/GuidanceDocuments/ UCM311176.pdf) (The draft guidance represents FDA’s proposed approach on this topic) 10 U.S. Food and Drug Administration, Cellular, Tissue and Gene Therapies Advisory Committee (2005) Meeting #38, Cellular Products for Joint Surface Repair, March 3–4. (http://www.fda.gov/ ohrms/dockets/ac/05/briefing/2005-4093B1_01.pdf; http://www. fda.gov/ohrms/dockets/ac/05/transcripts/2005-4093T1.htm; http:// www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4093T2_01.htm) 11 U.S. Food and Drug Administration Cellular, Tissue and Gene Therapies Advisory Committee (2009) Meeting #47, May 15, Clinical Issues Related to the FDA Draft Guidance Document: Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage (http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/ CellularTissueandGeneTherapiesAdvisoryCommittee/UCM155436. pdf; http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/ CellularTissueandGeneTherapiesAdvisoryCommittee/UCM224961.pdf) 12 U.S. Food and Drug Administration (2011) Guidance for Industry: Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage (http://www.fda.gov/downloads/Biologics BloodVaccines/GuidanceComplianceRegulatoryInformation/ Guidances/CellularandGeneTherapy/UCM288011.pdf) 13 ASTM F2451 (2010) Standard Guide for in vivo Assessment of Implantable Devices Intended to Repair or Regenerate Articular Cartilage (http://www.astm.org/Standards/F2451.htm) 14 ISO 10993-1 (2009) Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing (http://www.iso.org/iso/home/store/catalogue_ tc/catalogue_detail.htm?csnumber=44908) 15 ASTM F748-06 (2010) Standard Practice for Selecting Generic Biological Test Methods for Materials and Device (http:// www.astm.org/Standards/F748.htm) 0167-7799/$ – see front matter . Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.tibtech.2013.08.003 Trends in Biotechnology, December 2013, Vol. 31, No. 12
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Cartilage repair and replacement in the knee: a regulatory perspective J. Terrig Thomas1, Bruce S. Schneider1, Elizabeth L. Frank2, and Sylva J. Krizan2 1 2
Center for Biologics Evaluation and Research, FDA, Rockville, MD, USA Center for Devices and Radiological Health, FDA, Silver Spring, MD, USA
Background The number of investigational knee cartilage repair or replacement product submissions (hereafter referred to as cartilage products) received by the FDA is increasing. This trend may reflect the rise in cartilage repair publications and active product development (Figure 1). To describe its current thinking on cartilage products, the FDA recently finalized guidance entitled ‘Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage’. This article provides an overview of cartilage product regulation and the Cartilage Guidance document. Regulatory pathway for cartilage products The regulatory pathway for marketing approval of investigational cartilage products in the USA depends on the applicable legal definitions. Depending on its composition, a cartilage product may be defined as a tissue, non-tissue biologic, device, drug, or combination of two or more of these. If classification is unclear, the FDA encourages informal communications with its review staff, and the Office of Combination Products (OCP). In some cases, a formal Request for Designation (RFD) may be submitted to the OCP, whose decision is legally binding [1]. In addition, for human cells, tissues, and cellular and tissue-based products (HCT/Ps), the FDA Tissue Reference Group (TRG) considers questions posed by product developers and makes regulatory pathway recommendations [2]. A more detailed discussion of the regulatory processes relevant to cartilage products is available [3]. Tissues Tissues categorized as HCT/Ps are regulated by the Center for Biologics Evaluation and Research (CBER) under 21 CFR Part 1271 and Section 361 of the Public Health Service Act (PHSA). For regulation solely under Section 361 the following four criteria in Part 1271 must be met. The product: (i) must be minimally manipulated; (ii) must be intended for homologous use only; (iii) must not be combined with another drug or device (with some exceptions); and (iv) must not have a systemic effect, and must not be dependent upon metabolic activity of living cells for Corresponding author: Thomas, J.T. ([email protected]).
its primary function (unless use is either autologous or allogeneic in a first or second degree blood relative). FDA guidance regarding application of the various requirements of Part 1271 (21 CFR 1271) are available [4]. HCT/Ps not meeting all four criteria are regulated as drugs, biologic drugs, or medical devices. Biologic drugs For cartilage products regulated as biologic drugs, an Investigational New Drug (IND) application is necessary for clinical investigation. Prior to marketing, the product must be demonstrated to be safe, pure, potent, and effective, and approval of a Biologics License Application (BLA) is required. Guidance on biologics regulation is available [5]. Medical devices Medical devices reviewed by the Center for Devices and Radiological Health (CDRH) are categorized into three risk-based classes ranging from the lowest (Class I) to the highest (Class III) risk. Cartilage products regulated as devices are classified as Class III, and clinical studies conducted in the USA must be conducted under an Investigational Device Exemption (IDE). Prior to marketing, review and approval of a Pre-Market Approval (PMA) application are required. Guidance on the processes and data expectations for IDEs and PMAs is available [6]. Combination products In most cases, a combination product is ‘a product comprising two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity’ [21 CFR 3.2 (e)1]. A combination product can also be a product packaged separately, but intended for use only when combined with another approved product [21 CFR 3.2(e)2–4]. Assignment of the FDA Center with primary jurisdiction for a combination product typically is based on the primary mode of action through which the product achieves its therapeutic effect [21 CFR 3.4(a)]. If this is uncertain, the OCP designates the Center based on other, secondary factors [21 CFR 3.4(b)] [7]. FDA review approach for cartilage products CDRH/CBER reviewers collaborate to ensure guidance documents, standards, and review practices are consistent. Advice from outside experts is also sought on an ad hoc 665
Forum: Science & Society
Trends in Biotechnology December 2013, Vol. 31, No. 12
Lesion size/location (scaled to the clinical lesion). Appropriate endpoints (clinically relevant). Arthroscopic and/or magnetic resonance imaging (MRI) evaluations.
100 000 Key:
Carlage publicaons Carlage repair publicaons
10 000
The Cartilage Guidance [12] provides recommendations on appropriate animal models, based on the AC meeting discussions [10,11] and on the American Society for Testing and Materials (ASTM) standards on the assessment of devices for cartilage repair [13].
1000
100
10
1 1990–1995
1996–2000
2001–2005
2006–2010
TRENDS in Biotechnology
Figure 1. PubMed search showing the distribution of cartilage publications from 1990 to 2010. The number of publications containing the term ‘cartilage repair’ has increased more than those with the term ‘cartilage’.
basis. The FDA encourages product developers to schedule pre-IND/IDE submission meetings [8,9] to obtain FDA feedback on regulatory issues, product characterization, and the design of nonclinical and clinical studies. The FDA has held two public advisory committee (AC) meetings to discuss issues related to cartilage product regulation. In 2005, the FDA solicited advice on preclinical and clinical assessments of cartilage products [10] and published a draft guidance document. In 2009, at a second AC meeting [11], comments received on the draft guidance were discussed before the FDA published the final Cartilage Guidance [12]. The following provides an overview of this guidance. Product description In brief, for IDEs (see 21 CFR Part 812), information should be provided for the manufacture of the device component in sufficient detail to allow a judgment regarding quality control [21 CFR 812.20(b)] [3]. For INDs (see 21 CFR Part 312), adequate Chemistry, Manufacturing, and Control (CMC) information is required to assure the identity, purity, and stability of the product [21 CFR 312.23(a)] [7]. Please refer to the relevant guidance documents for further information [5,6,12]. Nonclinical data Nonclinical data, as listed below, are necessary to demonstrate an acceptable product safety profile prior to initiating clinical studies. Animal studies Biological response to the final product and/or components (e.g., cells and scaffold). Durability of therapeutic effect (e.g., repair of the lesion). Potential local/systemic adverse effects (e.g., product distribution, degradation, and tumorigenicity). Dose response (e.g., responses to material constituents and cell number). 666
Mechanical testing Where appropriate, major mechanical testing considerations for cartilage devices are: Ability of implant to withstand expected in vivo static and dynamic loading (e.g., compression, shear, and tension). Appropriate analysis of fixation method (e.g., producttissue integration strength). Propensity of implant to generate wear debris. Mechanical testing should include assessment immediately following implantation, throughout the repair process, and at completion of the study. Testing should compare repaired/regenerated tissue to control tissue. Biocompatibility testing Biocompatibility testing may be required to determine any potentially harmful physiological effects of the investigational device. For more information, the International Organization for Standardization (ISO) and ASTM standards provide overviews of the minimum required biocompatibility testing [14,15]. Clinical evaluation Ideally, clinical development of an investigational cartilage product proceeds through a series of exploratory (feasibility or Phases 1 and 2) and confirmatory (pivotal or Phase 3) clinical studies. Exploratory studies are designed to evaluate adverse events, failures, implantation technique, and bioactivity data. Addition of control groups may provide some indication of clinical efficacy, depending on sample size and magnitude of the treatment effect. The results should help design subsequent confirmatory trials by providing support for product design/dosage, surgical technique, eligibility criteria, clinical evaluations, primary endpoints, and long-term follow-up. Confirmatory studies should use a randomized, concurrent-controlled design, in which control subjects receive current standard-of-care [12]. Blinding of investigators, evaluators, and subjects is desirable but may not always be feasible. Primary efficacy endpoints should evaluate both joint pain and function, using appropriate scoring systems [e.g., the Knee Injury and Osteoarthritis Outcome Score (KOOS) and the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form2000] generally from 1 to 3 years following product administration. Confirmatory studies should be designed to demonstrate superiority of the product, in terms of improvements in both pain and function, compared to
Forum: Science & Society the active control. All adverse events, revisions, removals, and reoperations should be recorded to provide an adequate safety database. Subjects should be followed for safety and effectiveness for a minimum of 2 years, preferably longer, with additional follow-up required as part of postmarketing surveillance. Imaging studies are strongly encouraged to provide further information regarding product performance as well as scientific knowledge. At present, imaging studies are used as secondary endpoints, and the protocol should specify the X ray/MRI technique, the views to be taken, and evaluation methodology. Images should be interpreted by at least two independent (blinded) readers. Conceivably, research may yield validated surrogates for clinical outcomes comprising genomic, proteomic, metabolic, or other biomarkers, together with in vivo imaging data. Surrogate validations will depend on correlation with improvements in pain and function; a challenge that could be addressed collaboratively among sponsors and investigators. Please refer to the Cartilage Guidance [12] for more specific recommendations on clinical evaluation of cartilage products. Concluding remarks Basic and clinical research, combined with knowledge of the regulatory process, is critical to bring safe and effective cartilage products to market. The focus of the FDA review and regulatory decision making process is evaluation of the clinical benefit/risk profile for every investigational cartilage product. Product developers should communicate with the FDA early and often, both before (pre-IND/IDE) and following submission of the IND/IDE. Acknowledgments The authors wish to thank members of the CBER/CDRH Cross-Center Working Group and CBER/CDRH senior management for their valuable feedback and internal review of the manuscript.
References 1 U.S. Food and Drug Administration (2011) Guidance for Industry: How to Write a Request for Designation (RFD) (http://www.fda.gov/ downloads/RegulatoryInformation/Guidances/UCM251544.pdf) 2 U.S. Food and Drug Administration (2013) Vaccines, Blood and Biologics, Tissue Reference Group (http://www.fda.gov/ biologicsbloodvaccines/tissuetissueproducts/regulationoftissues/ ucm152857.htm) 3 Lee, M.H. et al. (2010) Considerations for tissue-engineered and regenerative medicine product development prior to clinical trials in the United States. Tissue Eng. B Rev. 16, 41–54
Trends in Biotechnology December 2013, Vol. 31, No. 12 4 U.S. Food and Drug Administration (2012) Vaccines, Blood and Biologics, Tissue Guidances (http://www.fda.gov/BiologicsBlood Vaccines/GuidanceComplianceRegulatoryInformation/Guidances/ Tissue/default.htm) 5 U.S. Food and Drug Administration (2013) Vaccines, Blood and Biologics, Guidance, Compliance, and Regulatory Information (Biologics) (http://www.fda.gov/cber/guidelines.htm) 6 U.S. Food and Drug Administration (2013) Medical Devices, Device Advice: Comprehensive Regulatory Assistance (http://www.fda.gov/ MedicalDevices/DeviceRegulationandGuidance/default.htm) 7 U.S. Food and Drug Administration (2006) Guidance for Industry and FDA Staff: Early Development Considerations for Innovative Combination Products (http://www.fda.gov/downloads/Regulatory Information/Guidances/ucm126054.pdf) 8 U.S. Food and Drug Administration (2012) Vaccines, Blood and Biologics, OCTGT Learn (http://www.fda.gov/BiologicsBloodVaccines/ NewsEvents/ucm232821.htm) 9 U.S. Food and Drug Administration (2012) Draft Guidance for Industry and FDA Staff Medical Devices: The Pre-Submission Program and Meetings with FDA Staff (http://www.fda.gov/downloads/Medical Devices/DeviceRegulationandGuidance/GuidanceDocuments/ UCM311176.pdf) (The draft guidance represents FDA’s proposed approach on this topic) 10 U.S. Food and Drug Administration, Cellular, Tissue and Gene Therapies Advisory Committee (2005) Meeting #38, Cellular Products for Joint Surface Repair, March 3–4. (http://www.fda.gov/ ohrms/dockets/ac/05/briefing/2005-4093B1_01.pdf; http://www. fda.gov/ohrms/dockets/ac/05/transcripts/2005-4093T1.htm; http:// www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4093T2_01.htm) 11 U.S. Food and Drug Administration Cellular, Tissue and Gene Therapies Advisory Committee (2009) Meeting #47, May 15, Clinical Issues Related to the FDA Draft Guidance Document: Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage (http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/ CellularTissueandGeneTherapiesAdvisoryCommittee/UCM155436. pdf; http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/ CellularTissueandGeneTherapiesAdvisoryCommittee/UCM224961.pdf) 12 U.S. Food and Drug Administration (2011) Guidance for Industry: Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage (http://www.fda.gov/downloads/Biologics BloodVaccines/GuidanceComplianceRegulatoryInformation/ Guidances/CellularandGeneTherapy/UCM288011.pdf) 13 ASTM F2451 (2010) Standard Guide for in vivo Assessment of Implantable Devices Intended to Repair or Regenerate Articular Cartilage (http://www.astm.org/Standards/F2451.htm) 14 ISO 10993-1 (2009) Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing (http://www.iso.org/iso/home/store/catalogue_ tc/catalogue_detail.htm?csnumber=44908) 15 ASTM F748-06 (2010) Standard Practice for Selecting Generic Biological Test Methods for Materials and Device (http:// www.astm.org/Standards/F748.htm) 0167-7799/$ – see front matter . Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.tibtech.2013.08.003 Trends in Biotechnology, December 2013, Vol. 31, No. 12
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