Guidance for Industry
 
 
Preparation of IDEs and INDs for 
Products Intended to Repair or 
Replace Knee Cartilage
 
 
 
 
 
 
 
 
 
 
 
Additional copies of this guidance are available from the Office of Communication, Outreach 
and Development (OCOD), (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-
1448, or by calling 1-800-835-4709 or 301-827-1800, or e-mail ocod@fda.hhs.gov, or from the 
Internet at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/default.htm. 
 
 
For questions on the content of this guidance, contact OCOD at the phone numbers or e-mail 
address listed above. 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
Center for Devices and Radiological Health 
December 2011  Contains Nonbinding Recommendations 
 
 
Table of Contents 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  PRODUCT DESCRIPTION............................................................................................2 
IV.  MANUFACTURING AND CMC INFORMATION.....................................................3 
A.  Device Component................................................................................................3 
B.  Cellular or Gene Therapy Product or Cellular Component of Combination 
Product...................................................................................................................3 
V.  NONCLINICAL DATA CONSIDERATIONS..............................................................4 
A.  Animal Data and Testing Considerations...........................................................4 
1.  Suitability of Animal Model(s).........................................................................5 
2.  Animal Report(s) to be Submitted....................................................................7 
B.  Mechanical Data and Testing Considerations....................................................8 
1.  Suitability of Mechanical Testing.....................................................................8 
2.  Mechanical Testing Report(s) to be Submitted................................................9 
VI.  BIOCOMPATIBILITY TESTING...............................................................................10 
VII.  CLINICAL STUDY PROTOCOLS..............................................................................10 
A.  Design...................................................................................................................10 
1.  Early Phase Clinical Studies...........................................................................10 
2.  Phase 3 or Pivotal Clinical Studies.................................................................11 
B.  Control Group.....................................................................................................12 
C.  Study Population.................................................................................................13 
D.  Study Efficacy Endpoints...................................................................................14 
E.  Investigational Product Implantation Procedures...........................................15 
F.  Follow-Up.............................................................................................................16 
G.  Adverse Experience (Risk) Reporting...............................................................16 
VIII.  REFERENCES................................................................................................................18 
i  Contains Nonbinding Recommendations 
 
Guidance for Industry 
 
Preparation of IDEs and INDs for Products Intended to Repair or 
Replace Knee Cartilage 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this 
topic.  It does not create or confer any rights for or on any person and does not operate to bind 
FDA or the public.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the appropriate FDA staff.  If you cannot identify the appropriate FDA staff, 
call the appropriate number listed on the title page of this guidance. 
 
I.  INTRODUCTION 
 
This guidance document provides to you, sponsors of an investigational device exemption 
application (IDE) or an investigational new drug application (IND), recommendations about 
certain information that should be included in a submission describing a product intended to 
repair or replace knee cartilage.  For the purposes of this document, a product intended to repair 
or replace knee cartilage, as with other cartilage repair or replacement products,1 may include a 
biologic, device, or combination product2 whose components would individually be regulated by 
the Center for Devices and Radiological Health (CDRH) or the Center for Biologics Evaluation 
and Research (CBER).3,4  This guidance finalizes the draft guidance of the same title dated July 
2007. 
 
This guidance supplements recommendations regarding IDE and IND submissions contained in 
other FDA publications (e.g., Guidance on Applications for Products Comprised of Living 
Autologous Cells Manipulated ex vivo and Intended for Structural Repair or Reconstruction 
dated May 1996, (Ref. 1)).  For general information on IDEs and INDs, see 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/I
nvestigationalDeviceExemptionIDE/default.htm and 
                                                 
1 Prostheses such as unicondylar or total knee implants are beyond the scope of this guidance.  Meniscus 
replacement productswhich are being studied for use in preventing cartilage damageare also beyond the scope 
of this guidance unless manufacturers propose new indications related to cartilage repair, replacement, or 
preservation. 
2 A combination product is a product composed of any combination of a drug and a device; a biological product and 
a device; a drug and a biological product; or a drug, device and a biological product.  For the definition of the term 
combination product, see Title 21 Code of Federal Regulations, Part 3 (21 CFR Part 3) at 21 CFR 3.2(e). 
3 Forward specific questions regarding product jurisdiction with respect to a combination product to the Office of 
Combination Products (OCP).  You may call OCP at 301-796-8930 or email OCP at combination@fda.gov.  
Information about the Request for Designation (RFD) program and guidance related to the regulation of 
combination products are available at the OCP website at http://www.fda.gov/CombinationProducts.  Forward 
questions regarding the applicability of specific regulations for articular cartilage repair or replacement products, for 
which jurisdiction has already been determined, to the Center with jurisdiction. 
4 Human cells, tissues, and cellular and tissue-based products (HCT/Ps) regulated solely under section 361 of the 
Public Health Service Act (PHS Act) (42 U.S.C. 264) and 21 CFR Part 1271 are beyond the scope of this guidance. 
1  Contains Nonbinding Recommendations 
 
http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/InvestigationalNew
DrugINDorDeviceExemptionIDEProcess/default.htm, respectively. 
 
We, FDA, typically regard investigational devices for articular cartilage repair or replacement to 
be significant risk devices (see 21 CFR 812.3(m)(1)) ( 812.3(m)(1)).  Therefore, if you intend to 
conduct clinical studies of these devices in the United States, you will likely need to submit to 
FDA an application for an IDE (21 CFR 812.20).  All investigational studies for cellular therapy 
products, except for HCT/Ps that meet the criteria specified in 21 CFR 1271.10(a), including 
products for articular cartilage repair or replacement, require submission of an IND  
(21 CFR 312.20) ( 312.20).  When an IND or IDE is required, you must comply with FDAs 
IND regulations (21 CFR Part 312) or IDE regulations (21 CFR Part 812), as appropriate, to 
proceed with clinical investigations of these products.  Institutional review board (IRB) approval 
alone is not sufficient to commence a clinical study in human subjects involving articular 
cartilage repair or replacement products (21 CFR 56.103). 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  
The use of the word should in FDAs guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND 
 
We prepared this guidance to address issues that may arise in the development of articular 
cartilage repair or replacement products.  This guidance also reflects input received from the 
public and the Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) at the 
March 3 to 4, 2005 CTGTAC meeting (Ref. 2) and May 15, 2009 CTGTAC meeting (Ref. 9). 
 
 
III.  PRODUCT DESCRIPTION 
 
For products subject to the IDE submission requirements in 21 CFR Part 812, you should, and in 
some cases are required to, provide in an IDE the following information to describe the 
investigational device: 
 
  A complete written description of the individual components and how any components 
interact either mechanically or chemically.  See  812.25(d) and 812.20(b)(2). 
  A description of the material(s) and any voluntary material standard(s) to which the 
material(s) conform.  See  812.25(d) and 812.20(b)(2).  Depending on the material, we 
may recommend biocompatibility testing, as described in section VI. of this document. 
  A description of anticipated changes to the device.  See  812.25(d) and 812.20(b)(2). 
  A list and description of all instruments (including trial components) unique to the 
implantation of the product, the material or voluntary material standard(s) to which they 
conform, and supporting engineering drawings or photographs of them.  See  
2  Contains Nonbinding Recommendations 
 
 812.25(d) and 812.20(b)(2).  You should provide evidence that the instrument 
materials are safe for limited contact with a breached surface, any instructions for 
assembly/disassembly (if applicable), and a statement regarding whether the instruments 
are re-usable or for single use only, and if re-usable, adequate instructions on cleaning 
and sterilizing the instruments.   
 
Depending on the particular design of the product, additional information may be appropriate: 
 
  For any concurrent control product or treatment, we recommend that you provide a 
written description, any available drawings and photographs, and information regarding 
materials from which the control product is manufactured. 
  Products regulated under an IND must include a description of the product into the 
Chemistry, Manufacturing, and Controls (CMC) section of the IND submission per  
 312.23(a)(7).  Recommendations for application of these regulations to cellular and 
gene therapy products are provided in the CMC guidances listed below in section IV.B. 
of this document. 
 
 
IV.  MANUFACTURING AND CMC INFORMATION 
 
A.  Device Component 
 
Under  812.20(b)(3), you must provide a description of the methods, facilities, and 
controls used for the manufacture, processing, packing, storage, and, where appropriate, 
installation of the device, in sufficient detail so that a person generally familiar with good 
manufacturing practices can make a knowledgeable judgment about the quality control 
used in the manufacture of the device. 
 
As part of that information, you should provide the following: 
 
  basic manufacturing information regarding product design issues; and 
  sterilization information for the finished device, as described in the FDA guidance 
entitled, Updated 510(k) Sterility Review Guidance K90-1; Final Guidance for 
Industry and FDA dated August 2002 (Ref. 3). 
 
B.  Cellular or Gene Therapy Product or Cellular Component of Combination 
Product 
 
Section 312.23(a)(7) directs the sponsor to provide manufacturing and CMC information 
commensurate with the phase of the investigation.  In addition, the current good tissue 
practice requirements in 21 CFR Part 1271 establish processing requirements applicable 
to all HCT/Ps, including those under IND. 
 
For a cellular or gene therapy product or cellular constituents of a combination product, 
we recommend that you refer to the following FDA guidances: 
 
3  Contains Nonbinding Recommendations 
 
  Guidance for Industry:  Guidance for Human Somatic Cell Therapy and Gene 
Therapy dated March 1998 (Ref. 4); 
  Guidance for FDA Reviewers and Sponsors:  Content and Review of Chemistry, 
Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy 
Investigational New Drug Applications (INDs) dated April 2008 (Ref. 5); and 
  Guidance for FDA Reviewers and Sponsors:  Content and Review of Chemistry, 
Manufacturing, and Control (CMC) Information for Human Gene Therapy 
Investigational New Drug Applications (INDs) dated April 2008 (Ref. 6). 
 
 
V.  NONCLINICAL DATA CONSIDERATIONS 
 
You should provide nonclinical data sufficient to establish scientific support for clinical 
investigation of your product, and to demonstrate an acceptable safety profile of your product 
prior to initiating a human clinical study (see  312.23(a)(8) for IND-specific requirements 
relating to the submission of pharmacology and toxicology information).  These data can be 
derived from animal studies, mechanical testing, or a combination of both.  You should choose 
the most appropriate testing to demonstrate the anticipated performance and address the safety 
issues raised by your product.  The type of studies will be dependent on the exact constituents of 
your product.  We encourage you to contact us about general and nonclinical testing to further 
define specific test recommendations.  We recommend you design testing strategies that combine 
animal and mechanical testing in single studies if such a strategy does not compromise the 
validity of the measurements, or the usefulness of the data. 
 
While a description and analysis of the individual components of a product consisting of multiple 
components is necessary, it is not sufficient as it does not provide information on how the final 
product functions and the interactions in vivo.  Because of this, the key nonclinical studies 
should ideally evaluate a version of the product that is identical to the product that is intended to 
be used in the clinical evaluations.  If this is not possible, you should provide a rationale that 
addresses the differences between the various versions of the product and why the nonclinical 
data resulting from an analysis of a different product is applicable in support of initiation of 
clinical studies.  In order to facilitate an appropriate review of the investigational application, we 
suggest that you provide information on the various versions of your product in tabular form that 
includes which nonclinical studies were conducted on each version, and where the study results 
are located in the IND or IDE submission. 
 
A.  Animal Data and Testing Considerations 
 
Generally, animal studies are used to assess the following issues: 
 
  Biological response to the product and the biological activity (proof of concept 
and safety data) of each component of a combination product.  You can use 
animal studies to demonstrate that a products components have the potential to 
contribute to the clinical efficacy of the final product. 
 
4  Contains Nonbinding Recommendations 
 
  Durability (length of time needed to assess repair of the cartilage lesion and the 
ability of the product to resist wear, degradation, withstand physiological relevant 
loads over time, etc.).  You can assess durability of the response in large animal 
studies.  Generally, studies that are a minimum of one year in length are 
recommended to provide an adequate period for completion of healing.  This 
duration is also generally sufficient to allow assessment of durability of the 
therapeutic response, and of the integrity of the product.  The study duration may 
vary depending on the product characteristics, type, and amount of data available.  
For example a product that takes longer to degrade may require longer follow-up 
for adequate characterization of the degradation profile.   
  Toxicology (potential for local and systemic toxicities due to a component of the 
product).  Local toxicities may be due to interactions of the product with the 
components of the joint, or degradation of the product in the joint.  Systemic 
toxicities may be due to cell or particle migration outside of the articular space.  
Potential for tumorigenicity or inappropriate differentiation of cellular products 
exists within or outside of the articular space.  
  Dose response (e.g., material constituents, cell number, and other characteristics, 
which may affect lesion repair).  Dose response can often best be assessed in large 
animal studies5 as a result of anatomic and biomechanical considerations. 
  Lesion size and location evaluated in the animal study should be scaled 
appropriately to mimic what will be studied clinically.  If multiple devices will be 
used clinically, this should be considered in the animal study design.  In addition, 
the lesion should be located in an analogous location in the animal study as 
intended for implantation in humans. 
  Appropriate endpoints should be used to design your animal study to mirror 
your clinical study; please consider incorporating secondary clinical endpoints 
from section VII.D. of this document into your study design (e.g., histology). 
  Use of arthroscopic and/or magnetic resonance imaging (MRI) evaluations.  
To reduce the number of animal sacrifices at each timepoint, it may be 
appropriate to provide interim arthroscopic assessments and/or MRI evaluations 
in the animal studies.  At the time of each sacrifice, the mechanical integrity of 
the cartilage should be assessed along with gross examination. 
 
Other important considerations for the animal study include: 
 
1.  Suitability of Animal Model(s) 
 
We recognize that choosing and determining the suitability of animal model(s) for 
evaluation of any specific product is difficult because there is no perfect animal 
model of articular cartilage injury.  As discussed at the March 2005 CTGTAC 
meeting (Ref. 2): 
                                                 
5 See ASTM standard F2451-05 (Reapproved 2010) Standard Guide for in vivo Assessment of Implantable Devices 
Intended to Repair or Regenerate Articular Cartilage.  http://www.astm.org/Standards/F2451.htm. 
5  Contains Nonbinding Recommendations 
 
  the scientific literature contains descriptions of numerous methods for 
evaluating the nonclinical behavior of native cartilage and, consequently, 
articular cartilage repair or replacement products; 
  not all of these methods may apply to a specific articular cartilage repair 
or replacement product; and 
  goats, sheep, and horses are the most frequently used large animal models 
for cartilage repair. 
 
Because a recommendation for a set of specific evaluations is not possible without 
detailed description of the articular cartilage repair, or replacement product, 
reference is made to the ASTM F2451-05, Standard Guide for in vivo 
Assessment of Implantable Devices Intended to Repair or Regenerate Articular 
Cartilage, reapproved by ASTM in 2010.6  This standard provides guidelines 
related to the development of animal models and mechanical testing.  We 
recommend that you consult this standard or the applicable scientific literature 
when designing animal studies.  Specifically, the standard contains a: 
 
  comparison of animal models (joint size and load, age, skeletal maturity);  
  articular cartilage defect types (location, size, type, depth, etc.); and 
articular cartilage defect locations;  
  discussion of articular cartilage defect preparation; description of gross 
and histological assessments; and  
  description of various mechanical evaluations and their applicability. 
 
Any of the large animal species referenced above may be appropriate in studies 
designed to support the activity and safety of your cartilage repair or replacement 
product.  However, we recommend that you choose the species after carefully 
considering the models ability to reflect the intended clinical use and provide a 
rationale for the animal model selected for your nonclinical study(ies) within your 
original IDE or IND application submission. 
 
We further recommend the use of pilot studies designed to confirm the suitability 
of testing a particular product in a specific animal species.  Several different 
animal studies and/or species may be necessary to adequately model functional 
aspects and potential toxicities of a single product.  However, the number of 
studies needed should be determined by relevant structural and biological 
characteristics of the product, not by the number of components of the product.  It 
may be possible to utilize a combination of small and large animal studies to 
evaluate degradation, durability, safety, and efficacy. 
 
In the case of a product containing human cells, studies performed in animals 
often require the use of either immunosuppressive agents to avoid rejection of the 
product, or the use of analogous cellular products in animals.  Analogous cellular 
                                                 
6 The standard is available at http://www.astm.org/Standards/F2451.htm or contact ASTM Customer Service at 
service@astm.org. 
6  Contains Nonbinding Recommendations 
 
products are cellular products derived from the animal species used for testing 
that are analogs of the ultimate clinical product in cellular characteristics and 
biologic activity.  You should characterize the level of analogy with the human 
product in preliminary studies prior to conducting a pivotal toxicology study with 
the analogous cellular product. 
 
We recommend that you design nonclinical testing of cartilage repair and 
replacement products that contain a cellular or gene therapy component following 
the principles provided in section VIII. of the FDA guidance entitled, Guidance 
for Industry:  Guidance for Human Somatic Cell Therapy and Gene Therapy 
dated March 1998 (Ref. 4), and if applicable, the recommendations provided in 
section IV. of the FDA guidance entitled, Guidance for Industry, Gene Therapy 
Clinical Trials  Observing Subjects for Delayed Adverse Events dated 
November 2006 (Ref. 10). 
 
2.  Animal Report(s) to be Submitted 
 
You should provide complete reports of any animal studies conducted using the 
investigational product7, whether adverse or supportive, relevant to the evaluation 
of the safety or effectiveness of the investigational product.  At a minimum, the 
following information should be included in the animal report: 
 
  the purpose of the study; 
  the rationale for the animal model used; 
  a detailed methods section, to include the creation, size, and location of 
the cartilage defect; 
  period of immobilization; 
  reports on gait analysis;  
  all tested parameters listed in section V. of this document, as applicable; 
and 
  pathological, histological, and radiological evaluations. 
 
In addition, you should explicitly describe any differences between the product 
used in the animal studies and the product proposed for clinical use in the IDE or 
IND. 
 
For each nonclinical laboratory study subject to the good laboratory practice (GLP) 
regulations under 21 CFR Part 58, you must include a statement that the study was 
conducted in compliance with the GLP regulations, or, if the study was not 
conducted in compliance with those regulations, a brief statement of the reason for 
the noncompliance ( 312.23(a)(8)(iii) for INDs and  812.27(b)(3) for IDEs).  For  
                                                 
7 Note that for IDE studies, sponsors must include reports of all prior clinical, animal, and laboratory testing of the 
device (21 CFR 812.27(a)).  Note that for IND studies, sponsors must provide adequate information to support the 
basis for concluding that it is reasonably safe to conduct clinical investigations (21 CFR 312.23(a)(8)). 
7  Contains Nonbinding Recommendations 
 
INDs, you must provide a full tabulation of data suitable for detailed review for 
each toxicology study that is intended primarily to support the safety of the 
proposed clinical investigation ( 312.23(a)(8)(ii)(b)). 
 
B.  Mechanical Data and Testing Considerations 
 
1.  Suitability of Mechanical Testing 
 
You should provide mechanical data for all articular cartilage repair or 
replacement products or a rationale addressing why limited mechanical testing 
coupled with complete animal study data are appropriate to establish an 
acceptable safety profile of the investigational product. 
 
The mechanical testing appropriate for your product may depend on the design, 
material, method of attachment to the subchondral bone and/or surrounding intact 
cartilage, and indication for use. 
 
Generally, the mechanical testing results should address the following: 
 
  ability of the implant to withstand expected in vivo static and dynamic 
loading (e.g., compression, shear, and tension); 
  analysis of fixation method (e.g., strength of integration between the 
product and surrounding native tissue); and 
  propensity to generate wear debris. 
 
Specifically, we recommend that you assess both the static mechanical behavior 
of the product by measuring the maximum recoverable compressive strain, the 
aggregate modulus (H ), the shear modulus (), and permeability () as well as 
A
the dynamic mechanical behavior of the product including an assessment of the 
complex shear modulus G*.  These assessments of the mechanical properties 
should include a determination of any relevant anisotropies and nonlinearities in 
your product.  In addition, you should determine the failure properties of your 
product.  For products that contain a degradable scaffold component(s), it will be 
important to assess the failure properties as a function of time.  Many mechanical 
testing methods may be used to measure the mechanical properties of your 
product, including, but not limited to, confined or unconfined compression and 
indentation.  We recommend that you consult with FDA to discuss the appropriate 
mechanical testing methodology for your product as well as refer to ASTM 
F2451-05 (reapproved 2010) for additional information regarding test methods. 
 
8  Contains Nonbinding Recommendations 
 
2.  Mechanical Testing Report(s) to be Submitted 
 
You should provide complete reports of any mechanical testing conducted on the 
investigational product8, whether adverse or supportive, that is relevant to the 
evaluation of the safety or effectiveness of the investigational product.  Each test 
report should include, but need not be limited to, the following elements: 
 
  identification of the components that comprised the product tested; 
  description of the apparatus used; 
  description of the procedures; 
  rationale supporting the testing environment as being a worst case 
condition; 
  rationale for the loading modes chosen; 
  study results; and 
  discussion of the results in terms of the expected in vivo and clinical 
performance of the system. 
 
You should also provide a comprehensive summary of all mechanical testing in 
addition to complete reports for each test, and include an assessment of the degree 
of cartilage breakdown.  This may be done visually after staining with India ink. 
 
We realize that some types of products are not capable of fully withstanding 
applied loads at the time of implantation (e.g., a cellular product held in place by a 
periosteal flap or a flexible scaffold that will eventually be populated by cells and 
ultimately form a load-bearing tissue).  For these products, it would be 
appropriate to characterize various mechanical properties at discrete time points 
following maturation in a suitable animal model.  You should initially assess the 
products ability to maintain its location within the loaded joint (analysis of 
fixation or interfacial strength), and subsequently continue to assess this 
characteristic while adding assessments of the newly-formed tissue aimed to 
determine its ability to bear applied loads.  Samples for these tests may consist of 
explanted regenerated tissue from the animal model or other appropriate samples 
as justified by the sponsor.  When there are differences between the proposed 
clinical product and the product tested, you should explain how or why the results 
are relevant in establishing the relative safety of the proposed product. 
 
Regardless of the evaluations which are performed, you should compare the 
properties of the repaired or regenerated tissue to control tissue (e.g., the cartilage 
collected from an unoperated control joint).  While it is understood that the repair 
tissue might have properties that differ from those of normal cartilage, you should 
describe why these differences might not be relevant to the in vivo and clinical 
behavior of the product. 
 
                                                 
As previously noted, for IDE studies, sponsors must include reports of all prior clinical, animal, and laboratory 
testing of the device (21 CFR 812.27(a)).  Note that for IND studies, sponsors must provide adequate information 
to support the basis for concluding that it is reasonably safe to conduct clinical investigations (21 CFR 312.23(a)(8)). 
9  Contains Nonbinding Recommendations 
 
 
VI.  BIOCOMPATIBILITY TESTING 
 
Depending on the material(s) used in the product, we may recommend biocompatibility testing.  
According to ISO-10993, Use of International Standard ISO-10993-1:2009, Biological 
Evaluation of Medical Devices Part-1:  Evaluation and Testing (Ref. 7) and/or ASTM F748-
06, Standard Practice for Selecting Generic Biological Test Methods for Materials and 
Devices9 may provide acceptable approaches for conducting biocompatibility testing.  You 
should include in the IND or IDE a complete test report describing the tests performed, the 
specific methods utilized, and the results. 
 
 
VII.  CLINICAL STUDY PROTOCOLS 
 
Clinical studies of articular cartilage repair or replacement products must be conducted in 
compliance with the IDE regulations, which include requirements to obtain FDA approval for 
studies of significant risk devices (21 CFR Part 812) or the IND regulations (21 CFR Part 312), 
as appropriate, as well as with the regulations as to informed consent (21 CFR Part 50) and the 
regulations as to IRBs (21 CFR Part 56) and other applicable regulatory requirements. 
 
A.  Design 
 
In general, the clinical development program for an investigational knee cartilage repair 
or replacement product should proceed through an orderly series of early phase and phase 
3 or pivotal clinical studies10.  The number of clinical studies as well as the specific 
design requirements is contingent upon multiple factors, including the characteristics of 
the investigational product, the route of product administration (e.g., implantation), the 
characteristics of the target population, and the proposed product indication.  This 
guidance provides only a broad outline of the major features to consider in designing a 
clinical study. 
 
1.  Early Phase Clinical Studies 
 
You should design early phase clinical studies that are conducted early in clinical 
development to obtain, in addition to any other features, the following 
information: 
 
  safety data (e.g., adverse experience reports, explant analyses where 
appropriate, revision procedure details); 
                                                 
9 http://www.astm.org/Standards/F748.htm. 
10 Exploratory, feasibility, phase 1, and phase 2, are all terms that have been used to modify clinical trials 
in various situations to describe early phase clinical trials.  Likewise phase 3 and pivotal have been used to 
refer to late phase clinical trials.  In an effort to increase simplicity, clarity, and readability, we will use early 
phase to denote all early phase clinical studies or trials, and we will use the phrase phase 3 or pivotal in this 
guidance to denote all late phase clinical studies or trials. 
10  Contains Nonbinding Recommendations 
 
  data assessing the ability to properly implant the product, including 
identification of any study procedures (including surgical procedure) that 
should be modified to optimize product administration/implantation; 
  bioactivity data, such as assessments of cartilage integrity based upon 
imaging results and/or biopsy findings; 
  data assessing the appropriateness of the target population; and 
  data providing information concerning the activity of the product in vivo 
or other information related to product activity that may be informative for 
future development, such as: 
o  product dose-response relationships; and 
o  product design-response characteristics. 
 
You should comprehensively evaluate early phase clinical study data to facilitate 
the design of phase 3 or pivotal studies.  At the conclusion of early phase clinical 
studies, you should be able to provide clinical data explaining the important 
aspects of the phase 3 or pivotal clinical studies that apply to the investigational 
product, such as:  
 
  data that support the product dose and design characteristics; 
  route of administration, including surgical implantation technique in the 
use of the product; 
  extent and nature of follow-up evaluations;  
  study subject sample size;  
  eligibility and ineligibility criteria; 
  choice of the major study endpoints; and 
  statistical assessments of the major study endpoints. 
 
An important consideration for an early phase clinical study of knee cartilage 
repair or replacement products is the potential use of a control group(s) to 
optimize the interpretation of the early phase findings.  In general, the most 
important clinical outcomes associated with use of these products are relief of 
pain and restoration of knee function, outcomes we believe are highly susceptible 
to bias due to assessment subjectivity.  The use of control groups in early phase 
studies may greatly facilitate the interpretation of the clinical study findings, even 
if  because of the nature of the studies  the statistical assessments lack the 
robustness or power to support phase 3 or pivotal clinical studies (for a more 
general discussion of controls groups in clinical studies of the products described 
in this guidance see section VII.B. of this document below). 
 
2.  Phase 3 or Pivotal Clinical Studies 
 
Phase 3 or pivotal clinical studies are designed to obtain hypothesis-testing data 
(i.e., to test a primary efficacy hypothesis and provide sufficient supportive data 
for that hypothesis as well as corresponding safety data).  Depending upon the 
characteristics of the investigational product, safety concerns may require sample 
sizes larger than one might estimate based solely upon the projected primary 
11  Contains Nonbinding Recommendations 
 
efficacy endpoint treatment effect.  Consequently, we recommend that you 
consider both efficacy and safety considerations in designing phase 3 or pivotal 
clinical studies. 
 
Typically, phase 3 or pivotal clinical studies use a randomized, controlled design.  
Whenever possible, we recommend that you use such a study design with 
endpoints ascertained in a blinded manner (e.g., subjects are blinded to treatment 
group, primary endpoints should be assessed in either a completely blinded 
manner or with the use of major endpoint evaluators who are blinded to the study 
treatment assignments).  However, alternative phase 3 or pivotal study designs 
may be considered.11  You should provide FDA with data (from your studies and 
applicable literature) and a rationale to support your phase 3 or pivotal study 
design prior to initiation of a phase 3 or pivotal study for any cartilage repair 
product. 
 
We believe that the clinical knowledge base generated for current potential active 
concurrent controls (such as microfracture) has not established a treatment effect 
size with precision sufficient to employ a non-inferiority trial design.  Therefore, 
we think that phase 3 or pivotal trials for these products should be designed and 
powered as superiority trials. 
 
Listed below in sections VII.B through G of this document, are important considerations 
for the design of both early phase and phase 3 or pivotal clinical studies. 
 
B.  Control Group 
 
Multiple options exist for the choice of a studys control group(s), and we recommend 
that you review the FDA guidance entitled, Guidance for Industry:  E 10 Choice of 
Control Group and Related Issues in Clinical Trials dated May 2001 (Ref. 8).  This 
guidance, while intended for biological products and drugs, contains concepts we believe 
may also be relevant to the clinical study of an investigational device intended for the 
repair or replacement of knee articular cartilage. 
 
In general, control groups may be broadly classified as either concurrent or historical.  
Rapid advances in surgical techniques and the medical care of damaged knees over the 
past several years suggest that you should generally use a concurrent control group to 
obtain the most informative clinical data.  We believe historical controls are insufficient 
for phase 3 or pivotal clinical studies of knee cartilage repair or replacement products. 
 
The most common types of concurrent control groups include placebo controls, sham-
surgery controls, active-comparator controls, or standard care controls.  If you choose an 
active comparator control, we recommend that you use one that is well accepted as 
                                                 
11 For cellular and gene therapy, and combination products regulated under section 351 of the PHS Act (42 U.S.C. 
262), please refer to the discussion of surrogate endpoints in the FDA guidance entitled, Guidance for Industry on 
Fast Track Drug Development Programs:  Designation, Development, and Application Review dated January 2006 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079736.pdf. 
12  Contains Nonbinding Recommendations 
 
standard treatment for the indication.  For example, the comparator may be an approved 
or licensed product or a well-accepted surgical procedure for the indicated condition.  
Comparator procedures may include the following:  microfracture, debridement, 
osteochondral autograft transplantation (e.g., mosaicplasty), autologous chondrocyte 
implantation, autogenous perichondral or periosteal grafts, and osteochondral allografts, 
depending on the standard treatment for the indication.  You should provide a rationale 
for the selected comparator(s).  This rationale should include the comparability of the 
investigational and control treatments with respect to the extent of the surgical procedures 
involved as well as the duration and extent of rehabilitation. 
 
A study could also include more than one comparator study arm.  For example, a 
controlled study could compare treatment effects across a range of investigational 
product dosages or compare treatment effects among a group of alternative 
procedures/products. 
 
We recommend that, for most studies, randomized controls be used such that the control 
group populations have lesions that are similar to the experimental group in terms of 
depth, size, and extent of cartilage/bone damage. 
 
C.  Study Population 
 
We recommend you pre-specify the following subject selection characteristics within a 
study protocols eligibility criteria: 
 
  age; 
  degree of pain; 
  presence or absence of osteoarthritis and method of diagnosis of osteoarthritis; 
  chronicity of lesion; 
  minimum and/or maximum degree of physical function; 
  location of articular lesion (e.g., medial femoral condyle, lateral femoral condyle); 
  depth of lesion; 
  size area of lesion (i.e., in cm2); 
  concomitant joint pathology (e.g., meniscal tear, ligament tear); and  
  whether there has been prior treatment for the lesion; and an assessment of 
general health status.  
 
In defining each of these characteristics, you should select unambiguous definitions, 
preferably based upon well-accepted evaluation techniques.  One acceptable way for 
determining subject eligibility by size and extent of the cartilage lesion is through use of 
the International Cartilage Rating System (ICRS), as described in the International Knee 
Documentation Committee (IKDC) Knee Examination Form-2000.12  You should 
provide a scientific rationale in your study protocol or supportive documents for selecting 
minimum values, maximal values, lesion depth, lesion size, and number of product(s) to 
                                                 
12 This form is contained in the ICRS Cartilage Injury Evaluation Package, available at 
http://www.cartilage.org/_files/contentmanagement/ICRS_evaluation.pdf. 
13  Contains Nonbinding Recommendations 
 
be implanted.  To determine subject eligibility by clinical parameters such as pain and 
clinical function, we recommend that you use an established, validated clinical 
measurement instrument such as those described in section VII.D. 
 
D.  Study Efficacy Endpoints 
 
We recommend that clinical studies assess the endpoints described in this section.  
However, the applicability of these endpoints depends on the characteristics of the 
investigational product and its method of administration (e.g., implantation). 
 
We believe that clinically meaningful endpoints, such as improvement in pain and 
physical function, provide the most persuasive evidence of efficacy.  Consequently, you 
should identify changes in pain and physical functioning as the primary endpoint for 
phase 3 or pivotal clinical studies.  Examples of measures that may be used to assess 
these endpoints include the: 
 
  Knee Injury and Osteoarthritis Outcome Score (KOOS)13; 
  IKDC Subjective Knee Evaluation Form-2000; 
  Cincinnati Knee Rating System; 
  Symptom Rating Form; and 
  Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). 
 
However, none of the above single validated instruments can be used to measure both 
joint pain and function.  Therefore, separate validated instruments are recommended for 
measurement of both joint pain and function (Ref. 10).  If you use a co-primary endpoint 
approach, then statistical success should be met by both endpoints in a manner that 
preserves the overall type 1 error. 
 
Secondary endpoints that may be studied include: 
 
  arthroscopic evaluation to assess: 
o  changes in the size, location, and grade of cartilage lesions both before 
and after debridement, if debridement is intended.  One acceptable 
method for assessing these endpoints is through use of the ICRS, as 
described previously in section VII.C above. 
o  the integrity of repaired tissue; and 
o  the binding of implanted investigational product to adjacent tissue, 
including assessments of stiffness/firmness based upon tissue probing. 
  assessment of the physical findings from examination of the knee joint, 
including: 
o  both passive and active range of motion; 
o  quadriceps muscle strength; 
o  alignment; 
o  degree of patellar subluxation; 
                                                 
13 This form is available from http://www.koos.nu/. 
14  Contains Nonbinding Recommendations 
 
o  degree of effusion; 
o  degree of crepitus; and 
o  degree of ligament laxity. 
  histologic evaluation at both short (e.g., six months) and long term (e.g., two 
years) follow-up in a subset of subjects to assess: 
o  matrix zonal organization; 
o  cell density; 
o  cell morphology (i.e., chondrocytic vs. fibroblastic); 
o  collagen types and concentration; 
o  aggrecan concentration, size, and composition; 
o  other proteoglycan concentrations; 
o  noncollagenous protein concentrations; and 
o  inflammatory response. 
  serological assessments for antibody formation and evidence of inflammation. 
  assessment of synovial fluid samples for cell count, sterility, and, as applicable, 
markers of inflammation and antibody formation. 
  joint/cartilage structure as assessed by MRI, for: 
o  articular surface integrity; 
o  thickness and volume of chondral surface; 
o  subchondral bone plate contour; 
o  thickness and volume of synovial membrane; and 
o  volume of synovial fluid. 
 
We recommend that the protocol specify which MRI techniques and views will be taken, 
and that the images be interpreted by at least two independent (blinded) readers with a 
third available for adjudication, if necessary.  A core facility to interpret images 
independently could also be considered.  The protocol or study supportive documents 
should include a clear, prospectively stated description of the plan for review of these 
images, and plans for resolving conflicting readings. 
 
E.  Investigational Product Implantation Procedures 
 
The clinical protocol and supportive documents must provide a detailed description of the 
procedures to be used in implantation of the investigational product ( 312.23(a)(6) and 
812.25(b)).  This description is especially critical in multi-center studies.  We 
acknowledge that many surgical procedures use techniques common to standard surgical 
practice and these procedures can be briefly summarized in the description of the 
investigational product implantation procedures.  Any unique procedures for implantation 
of the investigational product should be described in detail. 
 
For plans related to any surgical procedures, the clinical protocol should identify and 
provide details on the: 
 
15  Contains Nonbinding Recommendations 
 
  Surgical technique for both the investigational and control treatments, including 
the type of anesthesia, the size of the incision, the use of antibiotics and pain 
medications, and the maximum number of product(s) that may be implanted, as 
applicable.  We recommend that the surgical procedures be comparable, as much 
as possible, between treatment groups. 
  Plans for post-operative care.  Supportive documents should address the use of 
continuous passive motion; the duration, method, and frequency of weight 
bearing; the type, dose, and frequency of pain medication used; and the type and 
frequency of rehabilitation.  These factors should be standardized between/among 
treatment groups when possible.  If it is not possible to standardize the surgical 
technique or post-operative care regimen, all attempts to mitigate the potential 
introduction of bias and influence on the outcomes should be taken.   
 
F.  Follow-Up 
 
You should include sufficient follow-up information from your clinical study for all 
investigational products within a premarket approval application (PMA) or biologics 
license application (BLA).  For investigational products which are resorbed, degraded, or 
remodeled, the study subject follow-up duration should be based on information gathered 
from in vivo and in vitro nonclinical studies, and the natural history of the underlying 
target clinical condition.  We recommend a minimum of two-year follow-up clinical 
information (subject to the degradation profile of the product) be submitted with the 
PMA or BLA.  Data from an extended follow-up period provides an important 
component of the information to be contained within product labeling.  Therefore, the 
subjects enrolled in initial or early phase studies should continue to be followed during 
the period of phase 3 or pivotal studies or longer to provide some long-term follow-up 
information, which may be required as part of post-market surveillance, with a minimum 
of five years of follow-up.14 
 
G.  Adverse Experience (Risk) Reporting 
 
This section concerns adverse experience (AE) reporting by the investigator(s) to the 
sponsor ( 312.64 and 812.150(a)(1)).15  When an investigator reports AEs to the 
sponsor, the investigator should stratify the AEs by those general to any surgery, those 
related to knee surgeries (open vs. arthroscopic), and those specific to the investigational 
product.  We recommend that you incorporate definitions or descriptions of known or 
anticipated AEs into the case report forms (CRFs) to ensure uniform reporting.  You 
should also state in the protocol and CRFs that all subsequent surgical intervention, 
investigational product-related or not, should be reported and recorded. 
 
                                                 
14 Characteristics of individual products may result in the need for longer than typical follow-up, such as gene 
therapy products as described in Reference 10. 
15 For requirements regarding AE reporting by a sponsor to FDA, see  312.32 and 812.150(b)(1). 
16  Contains Nonbinding Recommendations 
 
For the purpose of this guidance, we define subsequent surgical interventions as follows: 
 
  Revision - a procedure that adjusts or in any way modifies or removes part of the 
original investigational product, with or without replacement of a component; it 
may include adjusting the position of the original investigational product.  If the 
investigational product is used/implanted in conjunction with an FDA approved 
product/component, a revision to any component, even to the approved 
component, should be reported as a revision.  
  Removal - a procedure where all or part of the original investigational product is 
removed with or without replacement. 
  Reoperation - any subsequent surgical procedure at the involved surgery site that 
does not involve removal, revision, modification, or addition of any component(s) 
to the product. 
17  Contains Nonbinding Recommendations 
 
VIII.  REFERENCES  
 
1.  Guidance on Applications for Products Comprised of Living Autologous Cells Manipulated 
ex vivo and Intended for Structural Repair or Reconstruction, May 1996 
http://www.federalregister.gov/articles/1996/05/28/96-13386/guidance-on-applications-for-
products-comprised-of-living-autologous-cells-manipulated-ex-vivo-and. 
2.  Cellular, Tissue, and Gene Therapies Advisory Committee Meeting, March 3, 2005 
http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4093T1.htm; March 4, 2005 
http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4093T2_01.htm. 
3.  Updated 510(k) Sterility Review Guidance K90-1; Final Guidance for Industry and FDA, 
August 2002 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm0
72783.htm. 
4.  Guidance for Industry:  Guidance for Human Somatic Cell Therapy and Gene Therapy, 
March 1998 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/CellularandGeneTherapy/ucm072987.htm. 
5.  Guidance for FDA Reviewers and Sponsors:  Content and Review of Chemistry, 
Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy 
Investigational New Drug Applications (INDs), April 2008 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/Xenotransplantation/ucm074131.htm. 
6.  Guidance for FDA Reviewers and Sponsors:  Content and Review of Chemistry, 
Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New 
Drug Applications (INDs), April 2008 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/CellularandGeneTherapy/ucm072587.htm. 
7.  Use of International Standard ISO-10993-1:2009, Biological Evaluation of Medical Devices 
Part 1:  Evaluation and Testing Within a Risk Management Process, October 2010 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/detail.cfm?standard__identificati
on_no=28430. 
8.  Guidance for Industry:  E 10 Choice of Control Group and Related Issues in Clinical Trials, 
May 2001 http://www.fda.gov/RegulatoryInformation/Guidances/ucm125802.htm. 
9.  Cellular, Tissue, and Gene Therapies Advisory Committee Meeting, May 15, 2009 
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOther
Biologics/CellularTissueandGeneTherapiesAdvisoryCommittee/ucm155430.htm. 
10. Guidance for Industry:  Gene Therapy Clinical Trials  Observing Subjects for Delayed 
Adverse Events, November 2006 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/CellularandGeneTherapy/ucm072957.htm. 
 
 
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