Guidance for Industry 

Preparation of IDEs and INDs for 

Products Intended to Repair or 

Replace Knee Cartilage 

DRAFT GUIDANCE 

This guidance document is for comment purposes only. 

Submit comments on this draft guidance by the date provided in the Federal Register notice 

announcing the availability of the draft guidance. Submit written comments to the Division of 

Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments. 

You should identify all comments with the docket number listed in the notice of availability that 

publishes in the Federal Register. 

For questions on the content of this guidance, contact Dr. Richard McFarland, Office of Cellular, 

Tissue and Gene Therapies, Center for Biologics Evaluation and Research, at 301-827-5102 or 

Mr. Aric Kaiser, Office of Device Evaluation, Center for Devices and Radiological Health, at 

240-276-3676. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Biologics Evaluation and Research 

Center for Devices and Radiological Health 

July 2007
Contains Nonbinding Recommendations 

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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: 

Office of Communication, Training and Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research 

Food and Drug Administration 

1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448 

Phone: 800-835-4709 or 301-827-1800 

Internet: http://www.fda.gov/cber/guidelines.htm 

or 

Office of Communication, Education, and Radiation Programs 

 Division of Small Manufacturers, International, and Consumer Assistance (DSMICA), 

HFZ-220 

Center for Devices and Radiological Health 

Food and Drug Administration 

1350 Piccard Drive, Rockville, MD 20850 

Phone: 800-638-2041 or 240-276-3150 

Internet: http://www.fda.gov/cdrh/guidance.html

Email: dsmica@fda.hhs.gov 

Fax: 240-276-3151 
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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 AND TESTING....................................................................... 4

A. Animal Data and Testing...................................................................................... 4 

1. Suitability of animal model(s) .................................................................... 5 

2. Animal report(s) to be submitted ................................................................ 6 

B. Mechanical Data and Testing .............................................................................. 6 

VI. BIOCOMPATIBILITY.................................................................................................... 8

VII. CLINICAL STUDY PROTOCOLS................................................................................ 8

A. Design..................................................................................................................... 8 

1. Exploratory Clinical Studies....................................................................... 8 

2. Confirmatory Clinical Studies.................................................................... 9 

B. Control Group..................................................................................................... 10 

C. Patient Population............................................................................................... 11 

D. Study Endpoints.................................................................................................. 12 

E. Investigational Product Administration ........................................................... 14 

F. Follow-Up............................................................................................................. 14 

G. Adverse Event (Risk) Reporting........................................................................ 15 

VIII. REFERENCES................................................................................................................ 16

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Guidance for Industry 

Preparation of IDEs and INDs for Products Intended to Repair or 

Replace Knee Cartilage 

This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) 

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, recommendations about certain information 

that should be included in an investigational device exemption (IDE) or investigational new drug 

application (IND) for 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 articular 

cartilage repair or replacement products,1

 may include a biologic, device, or combination 

product2

 whose components would be individually regulated by the Center for Devices and 

Radiological Health (CDRH) and the Center for Biologics Evaluation and Research (CBER).3,4

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” 

(Ref. 1)). For general information on IDEs and INDs, see 

http://www.fda.gov/cdrh/devadvice/ide/index.shtml and http://www.fda.gov/cber/ind/ind.htm, 

respectively. 

 

1

 Prostheses such as unicondylar or total knee implants are beyond the scope of this guidance. Meniscus 

replacement products—which are being studied for use in preventing cartilage damage—are also beyond the scope 

of this guidance unless manufacturers propose new indications related to cartilage repair, replacement, or 

preservation. 

2

 A combination product is comprised of two or more different types of regulated constituents (i.e., drug-device, 

drug-biologic, device-biologic, or drug-device-biologic). See Title 21 Code of Federal Regulations (CFR) 3.2(e) for 

further information on how combination products are defined by FDA. 

3

 Forward specific questions regarding the jurisdiction over a combination product to the Office of Combination 

Products (OCP) at 301-427-1934 or 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 

(http://www.fda.gov/oc/combination). 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/P’s) regulated solely under section 361 of the 

Public Health Service Act (42 U.S.C. 264) and 21 CFR Part 1271 are beyond the scope of this guidance. 

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We, FDA, typically regard investigational devices for articular cartilage repair or replacement to 

be significant risk devices (see 21 CFR 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 

IDE (21 CFR 812.20(a)). 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). When an IND 

or IDE is required, you must comply with FDA's 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 generally not sufficient to 

commence a clinical study in human subjects involving articular cartilage repair or replacement 

products (21 CFR 56.103). 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the FDA’s 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 FDA’s 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, CTGAC meeting (Ref. 2). 

In addition, we carefully considered the relevant statutory criteria for FDA decision-making and 

any possible burden you may incur in your attempt to address the issues and follow our 

recommendations in the guidance. We believe that we have considered the least burdensome 

approach to resolving the issues presented in this guidance document. If, however, you believe 

that there is a less burdensome approach, we recommend that you follow the procedures outlined 

in the “Guidance for Industry: A Suggested Approach to Resolving Least Burdensome Issues” 

(Ref. 3). 

III. PRODUCT DESCRIPTION 

For products subject to the IDE submission requirement 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. Depending on the particular design of the product, additional information 

may be appropriate: 

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• A complete written description of the individual components and how any components 

interact. See 21 CFR 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 21 CFR 812.25(d) and 812.20(b)(2). Depending on the 

material, we may recommend biocompatibility testing, as described in section VI. 

• A description of anticipated changes to the system. See 21 CFR 812.25(d) and 

812.20(b)(2). 

• A list of all instruments unique to the implantation of the product, the material and 

voluntary material standard to which they conform, and supporting magnified sketches or 

photographs of them. See 21 CFR 812.25(d) and 812.20(b)(2). 

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. 

For products regulated under an IND, we recommend that you incorporate a description of the 

product into the Chemistry, Manufacturing, and Controls (CMC) section of the IND submission 

as described in the final guidance listed below in section IV.B. and, when finalized, the two draft 

guidances listed in section IV.B. 

IV. MANUFACTURING AND CMC INFORMATION 

A. Device Component 

Under 21 CFR 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 guidance 

entitled, “Updated 510(k) Sterility Review Guidance K90-1; Final Guidance for 

Industry and FDA” (Ref. 4). 

B. Cellular or Gene Therapy Product or Cellular Component of Combination 

Product 

For a cellular or gene therapy product or cellular constituents of a combination product, 

we recommend that you refer to “Guidance for Industry: Guidance for Human Somatic 

Cell Therapy and Gene Therapy” (Ref. 5). When finalized, we also recommend that you 

refer to the following draft guidances: 

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• Draft “Guidance for Reviewers: Instructions and Template for Chemistry, 

Manufacturing, and Control (CMC) Reviewers of Human Somatic Cell Therapy 

Investigational New Drug Applications (INDs)” (Ref. 6); and 

• Draft “Guidance for FDA Review Staff and Sponsors: Content and Review of 

Chemistry, Manufacturing, and Control (CMC) Information for Human Gene 

Therapy Investigational New Drug Applications (INDs)” (Ref. 7). 

V. NONCLINICAL DATA AND TESTING 

You should provide nonclinical data sufficient to establish a scientific rationale for clinical 

investigation of your product, and to demonstrate an acceptable safety profile of your product 

prior to initiating a human clinical study (see 21 CFR 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 activities and address the safety issues raised by 

your product. We encourage you to 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. 

A. Animal Data and Testing 

Generally, animal studies are used to assess the following issues: 

• Biological response to products (e.g., biological activity [proof of concept and 

safety data] of each component of a combination product). You can use animal 

studies to demonstrate that a product's components have the potential to 

contribute to the clinical efficacy of the final product. 

• Durability of the response (e.g., length of time needed to assess repair of the 

cartilage lesion and durability of the repair). You can assess durability of the 

response in large animal studies. Generally studies of one year in length are 

recommended to provide an adequate period for completion of healing and 

assessment of durability. 

• Toxicology (e.g., potential for local and systemic toxicities due to 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 migration outside of the articular space. Potential for 

tumorigenicity or inappropriate differentiation of cellular products exist within or 

outside of the articular space. 

• Dose response (e.g., effect of variation in cell number or size of lesion). Dose 

response can be assessed in large animal studies. 

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1. Suitability of animal model(s) 

We recognize that choosing and determining the suitability of an 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): 

• 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. 

Any of these animal species 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 model’s 

ability to reflect the intended clinical use. 

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 

products are cellular products derived from the animal species used for testing 

that are analogs of the ultimate clinical product in phenotype 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 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. 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 “Guidance for Industry: Guidance for Human 

Somatic Cell Therapy and Gene Therapy” (Ref. 5). 

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 American Society for Testing and Materials (ASTM) 

F2451-05, “Standard Guide for in vivo Assessment of Implantable Devices 

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Intended to Repair or Regenerate Articular Cartilage,” approved April 1, 2005.5 

This standard provides guidelines related to the development of animal models 

and mechanical testing, and 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, articular cartilage defect types, 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. 

2. Animal report(s) to be submitted 

You should provide complete reports of any animal studies conducted using the 

investigational product, whether adverse or supportive, relevant to the evaluation 

of the safety or effectiveness of the investigational product. For 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 (21 CFR 312.23(a)(8)(ii)(b)). 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 

(21 CFR 312.23(a)(8)(iii) for INDs and 21 CFR 812.27(b)(3) for IDEs). You 

should specify in the animal report the purpose of the study and provide a detailed 

methods section, to include the creation and location of the cartilage defect, and 

supporting pathological, histological, and radiological evaluations. In addition, 

you should describe any differences between the product used in the animal 

studies and the product proposed for clinical use in the IDE or IND. 

B. Mechanical Data and Testing 

You should provide mechanical data for all articular cartilage repair products or a 

rationale addressing why mechanical testing is not necessary 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 

patient indication. However, you should generally provide mechanical testing results to 

address the ability of the implant to withstand expected in vivo static and dynamic 

loading (e.g., compression, shear, propensity to generate wear debris, analysis of fixation 

5 The referenced document is an American Society for Testing and Materials Standard. The standard is available at 

http://www.astm.org, or contact ASTM Customer Service at service@astm.org.

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method). We recommend that you compare the properties of the repaired or regenerated 

cartilage to those of normal articular cartilage. You should determine the aggregate 

modulus (HA), Poisson’s ratio (ν) and permeability (κ) of the solid phase. Permeability 

and aggregate modulus can be determined by confined compression creep testing, while 

all three of these properties can be determined from creep indentation tests using porous 

indentors (ASTM Standard F2451-05 contains information regarding suggested test 

methods). You should also include an assessment of the degree of cartilage breakdown. 

This may be done visually after staining with India ink or indentation probe “stiffness” 

evaluations. 

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 that ultimately form a 

load-bearing tissue). For these products, it would be appropriate to characterize various 

properties at discrete timepoints. You should initially assess the product’s ability to 

maintain its location within the loaded joint, and subsequently continue to assess this 

characteristic while adding assessments of the newly-formed tissue and its ability to bear 

applied loads. 

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. 

You should provide complete reports of any mechanical testing conducted on the 

investigational product, whether adverse or supportive, that are 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; 

• the set-up; 

• the procedures; 

• rationale supporting the testing environment as being a worst case condition 

• rationale for the loading modes chosen; 

• the results; and 

• a 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. 

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VI. BIOCOMPATIBILITY 

Depending on the material(s) used in the product, we may recommend biocompatibility testing. 

FDA's guidance entitled, “Use of International Standard ISO-10993, ‘Biological Evaluation of 

Medical Devices Part-1: Evaluation and Testing’” (Ref. 8) and/or ASTM F748-04, “Standard 

Practice for Selecting Generic Biological Test Methods for Materials and Devices”6

 may be 

recommended as 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. 

In addition, for any biological or drug component (e.g., bone morphogenic protein, bovine 

protein), we recommend that you follow any applicable FDA guidances. 

VII. CLINICAL STUDY PROTOCOLS 

Clinical studies of articular cartilage repair or replacement products must be conducted in 

compliance with IDE regulations (21 CFR Part 812) or IND regulations (21 CFR Part 312), along 

with Informed Consent (21 CFR Part 50) and IRB regulations (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 exploratory and 

confirmatory clinical studies. The number of clinical studies as well as the specific 

design requirements for each of these studies is contingent upon multiple factors, 

including the characteristics of the investigational product, the route of product 

administration, the characteristics of the target patient population and the proposed 

product indication. Consequently, this guidance provides only a broad outline of the 

major features to consider in designing a clinical study. 

1. Exploratory Clinical Studies 

You should design exploratory clinical studies that are conducted early in clinical 

development to obtain, in addition to any other features, the following 

information: 

• safety data; 

• data assessing the ability to properly administer the product, including 

identification of any study procedures that should be modified to optimize 

product administration; 

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 Id.

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• bioactivity data, such as assessments of cartilage integrity based upon 

imaging results and biopsy findings; 

• data assessing the appropriateness of the target patient 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 

o product design-response characteristics 

You should comprehensively evaluate exploratory clinical study data to facilitate 

the design of confirmatory studies. At the conclusion of exploratory clinical 

studies, you should be able to provide clinical data explaining the important 

aspects of the proposed confirmatory clinical studies that apply to the 

investigational product, such as: 

• data that support the product dose and design characteristics;

• route of administration, including surgical 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 exploratory clinical study of knee cartilage 

repair or replacement products is the use of a control group(s) to optimize the 

interpretability of the exploratory 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 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 expected of 

confirmatory clinical studies. 

2. Confirmatory Clinical Studies 

Confirmatory 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 render a larger 

sample size appropriate than one might estimate based solely upon the size of the 

projected primary efficacy endpoint treatment effect. Consequently, we 

recommend that you consider both efficacy and safety considerations in designing 

confirmatory clinical studies. 

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Typically, confirmatory clinical studies utilize a randomized, controlled design. 

Whenever possible, we recommend that you utilize a randomized, controlled 

study design with endpoints ascertained in a blinded manner (e.g., primary 

endpoints should be performed in either a completely blinded manner or with the 

use of major endpoint evaluators who are blinded to the study treatment 

assignments). However, alternative confirmatory study designs may be 

considered; as described, for example, in existing FDA guidance for products 

regulated under IND.7 You should provide us with data (from your studies and 

applicable literature) and a rationale to support your confirmatory study design 

prior to initiation of a confirmatory study for any cartilage repair product. 

Listed below in section VII.B through G are important considerations for the design of 

both exploratory and confirmatory clinical studies. 

B. Control Group 

Multiple options exist for the choice of a study’s control groups, and we recommend that 

you review the “Guidance for Industry: E10 Choice of Control Group and Related Issues 

in Clinical Trials” (Ref. 9). This guidance, while intended for biological products and 

drugs, contains concepts which, we believe, may also be relevant to the clinical study of 

an investigational device-biologic combination product. 

In general, control groups may be broadly divided into either concurrent or historical 

controls. 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 

rarely sufficient for confirmatory clinical studies of knee cartilage repair or replacement 

products. 

The most common types of concurrent control groups include placebo controls, shamsurgery 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 

standard treatment for the indication. For example, this 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. 

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 For cell, gene therapy, and combination products regulated under section 351 of the Public Health Service Act (42 

USC 264), please refer to the discussion of surrogate endpoints in FDA's “Guidance for Industry on Fast Track 

Drug Development Programs: Designation, Development, and Application Review” dated January 2006 

(http://www.fda.gov/cber/gdlns/fsttrk.pdf). 

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You should provide a rationale for the selected comparator(s). This rationale should 

include the comparability of the experimental 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. 

“Sham controlled studies” represent one study design and choice of control group which 

may allow for discrimination of patient outcomes caused by the test treatment from 

outcomes caused by other factors such as patient or observer expectations. This type of 

study design could be considered in studies with subjective endpoints such as reduction 

in patient-reported symptoms. Sham surgical procedures/treatments involve more risk 

than the placebo control arm in drug trials and should be used in limited circumstances. 

This study design should only be considered when it is methodologically necessary, i.e. 

when designs that are unblinded are methodologically unacceptable (e.g., because 

endpoints are subjective) and when a “no treatment” control is methodologically 

required. Furthermore, the withholding of treatment should not lead to serious harm, 

such as death or irreversible morbidity. FDA recognizes that it may be difficult for 

sponsors to develop a clinical study design with a sham control arm that investigators, 

institutional review boards, and patients believe is ethical; for this reason, studies 

involving a sham control arm should be carefully considered and planned. Additionally, 

if a sham procedure/treatment is being considered in a clinical investigation involving 

children, the requirements of 21 CFR Part 50 Subpart D (Subpart D) also apply. 

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. Patient Population 

We recommend you prespecify the following patient selection characteristics within a 

study protocol’s eligibility criteria: 

• degree of pain; 

• presence or absence of osteoarthritis and method of diagnosis of osteoarthritis; 

• 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. 

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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-2000.8

 You should provide 

a scientific rationale in your study protocol or supportive documents for selecting 

minimum values, maximal values, lesion depth, and lesion size. To determine subject 

eligibility by clinical parameters such as pain and clinical function we recommend that 

you use an established clinical measurement instrument such as those described in section 

VII.D. 

D. Study 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. 

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/or physical functioning as the primary endpoint for 

confirmatory clinical studies. Examples of measures that may be used to assess these 

endpoints include the: 

• Knee injury and Osteoarthritis Outcome Score (KOOS); 

• IKDC Subjective Knee Evaluation Form-2000; 

• Cincinnati Knee Rating System; 

• Symptom Rating Form; and 

• Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). 

Depending on the primary abnormality in the target population and other study design 

characteristics, we recommend that you use change in knee pain and/or physical 

functioning as the single primary endpoint in confirmatory studies. If you use a coprimary approach, then statistical success should be met in both endpoints in a manner 

that preserves the overall type 1 error. 

Secondary endpoints that may be studied include: 

• arthroscopic assessments of 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. 

8

 This form is contained in the ICRS Cartilage Injury Evaluation Package, available at 

http://www.cartilage.org/_files/contentmanagement/ICRS_evaluation.pdf. 

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• 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 presence of patellar subluxation 

o presence and degree of effusion 

o alignment 

o presence and degree of crepitus 

o presence and degree of ligament laxity 

• arthroscopic evaluation to assess: 

o the integrity of repaired tissue 

o the binding of implanted investigational product to adjacent tissue, including 

assessments of stiffness/firmness based upon tissue probing 

• 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 type I or type II collagen concentration 

o Aggrecan concentration, size, and composition 

o Dermatan sulfate proteoglycan concentration 

o noncollagenous protein concentrations (fibronectin, tenascin) 

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 magnetic resonance imaging (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 

o volume of synovial fluid 

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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. 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 Administration 

The clinical protocol and supportive documents must provide a detailed description of the 

procedures to be used in administration of the investigational product. See 

21 CFR 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 administration procedures. Any unique 

procedures for administration 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: 

• Surgical technique for both the investigational and control treatments, including 

the type of anesthesia, the size of the incision, and the use of antibiotics and pain 

medications, 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. 

F. Follow-Up 

You should include sufficient follow-up information for all investigational products 

within a premarket approval application (PMA) or 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, as well as 

from information based upon the natural history of the underlying, target clinical 

condition. However, even in this situation, we recommend that the PMA or BLA include 

two-year follow-up safety information on a subset of study subjects (this subset of 

subjects could be from initial, exploratory clinical studies). 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 exploratory studies 

should continue to be followed during the period of confirmatory studies so that you 

ultimately provide some long-term follow-up information from these initial studies. For 

reference, guidance on the length of follow-up for gene therapy products is available in 

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the “Guidance for Industry: Gene Therapy Clinical Trials - Observing Participants 

for Delayed Adverse Events” (Ref. 10). 

For investigational products which are not reabsorbed or degraded, a longer duration of 

patient follow-up is recommended to document safety outcomes. In this situation, 

generally five years of patient follow-up is recommended. This may be initiated during 

the pre-market phase and continued post-market. 

G. Adverse Event (Risk) Reporting 

This section concerns adverse event (AE) reporting by the investigator(s) to you. See 

21 CFR 312.64 and 812.150(a)(1).9 When an investigator reports AEs to you, 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 interventions, investigational productrelated or not, should be reported and recorded. 

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, modification, or addition of any component(s) to the 

product. 

9

 For requirements regarding adverse event reporting by the sponsors to FDA, see 21 CFR 312.32 and 

812.150(b)(1). 

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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.fda.gov/cber/gdlns/gdexv.pdf). 

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. Guidance for Industry: A Suggested Approach to Resolving Least Burdensome Issues, September 

2000 (http://www.fda.gov/cdrh/ode/guidance/1188.html). 

4. Updated 510(k) Sterility Review Guidance K90-1; Final Guidance for Industry and FDA, August 

2002 (http://www.fda.gov/cdrh/ode/guidance/361.html). 

5. Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy, March 1998 

(http://www.fda.gov/cber/gdlns/somgene.pdf). 

6. Draft Guidance for Reviewers: Instructions and Template for Chemistry, Manufacturing, and 

Control (CMC) Reviewers of Human Somatic Cell Therapy Investigational New Drug Applications 

(INDs), August 2003 (http://www.fda.gov/cber/gdlns/cmcsomcell.pdf).* 

7. Draft Guidance for FDA Review Staff and Sponsors: Content and Review of Chemistry, 

Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New 

Drug Applications (INDs), November 2004 (http://www.fda.gov/cber/gdlns/gtindcmc.pdf).* 

8. Guidance on Use of International Standard ISO-10993, “Biological Evaluation of Medical Devices 

Part 1: Evaluation and Testing,” May 1995 (http://www.fda.gov/cdrh/g951.html). 

9. Guidance for Industry: E10 Choice of Control Group and Related Issues in Clinical Trials, May 

2001 (http://www.fda.gov/cber/gdlns/clincontr0501.htm).** 

10. Guidance for Industry: Gene Therapy Clinical Trials – Observing Participants for Delayed 

Adverse Events, November 2006 (http://www.fda.gov/cber/gdlns/gtclin.pdf). 

*These draft guidances, when finalized, will represent FDA’s current thinking on their respective topics. 

**International Conference on Harmonization document. 

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