Guidance for Industry
 
 
Cellular Therapy for Cardiac Disease
 
 
 
 
 
 
 
 
 
 
 
 
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 email 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 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 
October 2010  Contains Nonbinding Recommendations 
 
Guidance for Industry 
 
Cellular Therapy for Cardiac Disease 
 
 
Additional copies of this guidance are available from: 
 
Office of Communication, Outreach and Development, 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 
E-mail:  ocod@fda.hhs.gov 
Internet:  http://www.fda.gov/cber/guidelines.htm 
or 
 Division of Small Manufacturers, International, and Consumer Assistance, HFZ-220 
Center for Devices and Radiological Health 
Food and Drug Administration 
1350 Piccard Drive, Rockville, MD 20850 
Phone:  800-638-2041 
Fax:  240-276-3151 
Email:  dsmica@fda.hhs.gov 
Internet: http://www.fda.gov/cdrh/guidance.html  Contains Nonbinding Recommendations 
 
Table of Contents 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................1 
III.  PRODUCT DESCRIPTION AND MANUFACTURING INFORMATION..............2 
IV.  PRECLINICAL DATA AND TESTING........................................................................3 
A.  Preclinical Testing of Cellular Products for Cardiac Repair...........................3 
B.  Model Selection and Data Reports......................................................................5 
1.  Use of In Vitro Data..........................................................................................5 
2.  Small Animal Models.......................................................................................5 
3.  Large Animal Models.......................................................................................6 
4.  Study Duration..................................................................................................6 
5.  Animal Report(s) to be Submitted in the IND..................................................6 
C.  Leveraging Data....................................................................................................7 
V.  DELIVERY SYSTEM EVALUATION AND TESTING.............................................7 
A.  Regulatory Considerations...................................................................................7 
1.  Master Files.......................................................................................................7 
2.  Identification.....................................................................................................8 
3.  Prior Information..............................................................................................8 
B.  Preclinical Testing of the Delivery System.........................................................8 
1.  Test Conditions.................................................................................................8 
2.  Data Reporting..................................................................................................9 
3.  In Vitro Testing.................................................................................................9 
4.  Delivery System-Patient Biocompatibility.......................................................9 
5.  Delivery System-Product Biocompatibility....................................................10 
6.  Preclinical In Vivo Studies.............................................................................10 
7.  Sterilization.....................................................................................................10 
8.  Shelf Life........................................................................................................10 
C.   Catheter Labeling...............................................................................................11 
VI.  CLINICAL TRIAL DESIGN.........................................................................................11 
A.  Subject Population..............................................................................................11 
1.  Refractory Angina/Ischemia...........................................................................11 
2.  Acute Ischemia/Infarction...............................................................................12 
3.  Heart Failure...................................................................................................12 
4.  General Requirements.....................................................................................12 
B.  Product Administration......................................................................................13 
C.  Safety Monitoring...............................................................................................13 
1.  Cardiac Markers..............................................................................................13 
2.  Arryhthmias and Conduction Abnormalities..................................................14 
3.  Myocardial Perforation/Pericardial Effusion..................................................14 
4.  Unique Monitoring Requirements..................................................................14 
i  Contains Nonbinding Recommendations 
 
5.  Stopping Rules................................................................................................14 
6.  Duration of Follow-Up...................................................................................15 
D.  Study Endpoints..................................................................................................15 
1.  Refractory Angina/Ischemia...........................................................................15 
2.  Acute Ischemia/Infarction...............................................................................16 
3.  Heart Failure...................................................................................................16 
4.  Unique Endpoint Considerations....................................................................16 
E.  Choice of Control................................................................................................17 
1.  Controls for Surgical Administration..............................................................17 
2.  Controls for Percutaneous Administration......................................................17 
F.  Informed Consent in Trials Involving Long-term Follow-up Observations.18 
G.  Statistical Considerations...................................................................................19 
VII.  REFERENCES................................................................................................................21 
APPENDIX:  IN VITRO TESTING OF THE DELIVERY DEVICE...................................22 
ii  Contains Nonbinding Recommendations 
 
Guidance for Industry 
 
Cellular Therapy for Cardiac Disease 
 
 
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 
 
We, FDA, are issuing this guidance to provide you, sponsors who are developing cellular 
therapies for the treatment of cardiac disease, with recommendations on the design of 
preclinical1 and clinical studies, and on the chemistry, manufacturing, and controls (CMC) 
information to include in an Investigational New Drug application (IND) for cellular therapy for 
cardiac disease.  This guidance also provides recommendations regarding the information that 
you should submit on the products delivery system.  Sponsors should consult with FDA 
concerning the regulatory pathway for the use of cell selection devices.   
 
This guidance finalizes the draft guidance entitled Guidance for Industry:  Somatic Cell 
Therapy for Cardiac Disease dated March 2009 (April 2, 2009, 74 FR 14992).   
 
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 
 
Despite advances in medical and surgical therapies, heart disease remains a major cause of 
morbidity and mortality.  There are an increasing number of patients with significant morbidity 
despite optimal medical management.  Researchers are studying whether cellular therapy may be 
capable of repairing a diseased heart through mechanisms such as modulation of paracrine 
pathways or regeneration of cardiac tissues.  As the field progresses, more data from Phase 1 and 
                                                 
 
1 For the purposes of this guidance, the term preclinical includes in vitro, in vivo and bench testing as described in 
Sections IV and V of this guidance. 
1  Contains Nonbinding Recommendations 
 
Phase 2 clinical trials (which collectively may be referred to as early phase clinical trials) 
should provide an enhanced understanding of cardiac repair mechanisms. 
 
Cellular therapies for the treatment of cardiac disease generally meet the definition of biological 
product in section 351(i) of the Public Health Service Act (42 U.S.C. 262(i)), and are regulated 
by the Center for Biologics Evaluation and Research (CBER).  Intravascular catheters and other 
drug and biologic delivery systems generally meet the definition of device under section 
201(h) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321(h)).   
 
FDA expects that these cellular therapies and their dedicated delivery systems would meet the 
definition of a combination product under 21 CFR 3.2(e), either by being co-packaged or, if 
marketed separately, by using labeling that indicates they are intended for use together.  Based 
on available information, the cellular therapy generally would provide the primary mode of 
action of the combination product and the lead center typically would be CBER in accordance 
with 21 CFR 3.4.2 
 
For a combination product, a single investigational application is generally sufficient.  For 
cellular therapies and their dedicated delivery systems, this generally would be an IND.   The 
IND application should contain the information as described in this guidance on the biological 
product and on the delivery system, along with any other information as required by the 
applicable regulations.  CBER and CDRH intend to consult or collaborate on the IND review, as 
appropriate for the science and technology of the combination product.   
 
For a combination product, one marketing application is also generally sufficient for FDA review 
and marketing authorization.  However, sometimes two marketing applications may be 
necessary.  You should consult with FDA regarding your particular product.  FDA encourages 
sponsors to initiate a discussion regarding the number and type of marketing applications during 
product development.  For additional information, see FDA Guidance for Industry and FDA 
Staff:  Early Development Considerations for Innovative Combination Products dated 
September 2006 (Ref. 1). 
 
 
III.  PRODUCT DESCRIPTION AND MANUFACTURING INFORMATION 
 
Under Title 21 Code of Federal Regulations (CFR) 312.23(a)(7)(i), the CMC section of your 
IND must include sufficient information, as appropriate for the phase of the investigation, to 
assure the proper identification (identity testing), quality, purity, and strength (potency) of the 
investigational product.  You must provide a description of the product and the manufacturing 
process, along with information concerning the safety and quality testing performed on the 
product prior to administration (21 CFR 312.23(a)(7)(iv)).  The types of CMC information 
needed to support an IND for the use of cellular products in cardiac disease are similar to those 
                                                 
 
2 Primary mode of action is defined at 21 CFR 3.2(m) and discussed in the final rule for Definition of Primary Mode 
of Action of a Combination Product (Aug. 25, 2005, 70 Fed. Reg. 49848), available on the FDAs website at 
http://www.fda.gov/OHRMS/DOCKETS/98FR/05-16527.htm, (Accessed Aug. 23, 2010). 
2  Contains Nonbinding Recommendations 
 
required for cellular products for other indications.  You should provide detailed descriptions of, 
and where necessary, data to support, the following:   
 
  cell source; 
  collection methods; 
  processing methods; 
  ancillary materials; 
  formulation; 
  testing methods; 
  criteria to release cell product for administration; 
  storage/shipping conditions; 
  stability; 
  segregation procedures to prevent cross contamination; and 
  container labeling (in process and final product) 
 
One common processing step for cellular products is the use of immunomagnetic selection by 
means of monoclonal antibodies and paramagnetic microspheres to yield a cell population 
enriched for a specific cell surface antigen.  Antibodies used in this process should be 
demonstrated to be free of adventitious agents and of appropriate quality to function as intended.  
You should also provide safety and quality information about the selection system/cell separation 
system that you have chosen.  If these data exist in previous submissions to FDA by a sponsor 
other than yourself, you must obtain a signed letter of cross reference from that person to support 
the use of the selection system or antibody and submit this as part of your IND (21 CFR 
312.23(b)). 
 
For information concerning the data necessary to establish the biocompatibility of the cellular 
product with the delivery system please see Section V of this guidance.   
 
For further information on the preparation of the CMC section of an IND, you may refer to the 
FDA guidances entitled 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. 2) and Guidance for 
Industry:  Guidance for Human Somatic Cell Therapy and Gene Therapy dated March 1998 
(Ref. 3). 
 
 
IV.  PRECLINICAL DATA AND TESTING 
 
A.  Preclinical Testing of Cellular Products for Cardiac Repair 
 
Preclinical safety evaluation is required for all new investigational products prior to their 
use in clinical studies (21 CFR 312.23(a)(8)).  Prior to initiating a clinical trial, you 
should provide sufficient preclinical data to establish a scientific rationale for clinical 
investigation of your product and to demonstrate an acceptable safety profile of your 
product and its delivery system.  These data are generally derived from animal studies, 
although data from in vitro testing of the cellular product are often important in refining 
3  Contains Nonbinding Recommendations 
 
the animal study design.  You should choose the most appropriate studies to demonstrate 
the activity and address the safety issues raised by your product.  These safety issues 
could include issues raised by the chosen route of administration and the delivery system.  
We, FDA, encourage you to design testing strategies that combine testing of the cellular 
product and the delivery system in single studies if such a strategy does not compromise 
the validity of the collected measurements or the usefulness of the data. 
 
Generally, animal studies are used to assess the following: 
 
  biological response to products (e.g., evidence of biological activity for proof-of-
concept and safety studies); 
  durability of response (e.g., length of time needed to assess the effect of treatment on 
the heart and the durability of that effect); 
  toxicology (e.g., potential for the product to cause local and systemic adverse findings 
of the product).  Local adverse findings may be due to interactions of the product with 
the heart.  Systemic adverse findings may be due to cell migration outside of the 
pericardial area.  The potential for tumorigenicity or inappropriate differentiation of 
cellular products may exist within the heart or in other locations where the product 
has migrated. 
  dose response (e.g., effect of variation in cell number on cardiac repair or function) 
 
The biological activity of cellular products in vivo can be determined by their tissue of 
origin, level of differentiation, and extent of manufacturing (level of manipulation) in 
combination with the microenvironmental milieu in which they are placed in vivo. The 
tissue of origin, level of differentiation, and extent of manufacturing are characteristics 
unique to a particular product and can be controlled by the manufacturing process.  
However, the effects of microenvironmental cues on the biological action of a specific 
cellular product can only be assessed by use in animal models of cardiac disease.  Such 
cues may be determined by the pathophysiology of the disease and the route of 
administration used for the cellular product. 
 
Cellular therapies can be administered using various routes of administration and 
numerous delivery systems, including, but not limited to:  (1) direct, syringe-and-needle 
injection of cellular products through the exposed epicardial surface into the subjacent 
myocardium during concomitant thoracic surgery; (2) infusion of cellular products into 
coronary arteries; (3) intramyocardial injection of cell suspensions through cardiac 
catheters; and (4) intravenous delivery.  The design of preclinical studies for these 
products typically includes an attempt to model the biological activities of a specific 
cellular product using the intended clinical delivery system in a specific clinical 
condition. 
 
If the delivery system to be used in the study is presently cleared or approved by the FDA 
for delivery to tissues targeted in the study, and if you have obtained a signed letter of 
cross reference for the delivery device (21 CFR 312.23(b)), additional preclinical studies 
that assess the safety and operability of the delivery system may not be necessary.  All 
preclinical studies that assess the ability of the delivery system to be deployed, to be 
4  Contains Nonbinding Recommendations 
 
retrieved, and to deliver the cellular product should evaluate the following device-specific 
endpoints: 
 
  damage to the site of delivery system introduction/retrieval, the access vasculature, 
the site(s) of product delivery, and any significant intermediate structures (e.g., the 
aortic and/or mitral valve), using gross pathology and histopathology as appropriate; 
  delivery system handling characteristics (e.g., flexibility, kink resistance, radiopacity, 
compatibility with accessory devices, and ease of insertion/removal); and 
  damage to the delivery system as a result of simulated use. 
 
Studies performed in animals often require the use of either immunosuppressive agents to 
avoid rejection of the human cellular 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 the pivotal preclinical studies 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 animal 
studies and/or species may be necessary to adequately evaluate functional endpoints, as 
well as any potential adverse findings that are observed following administration of an 
investigational product.  However, the number of studies needed should be determined by 
relevant biological characteristics of the product.  All differences in manufacturing and 
the final product characteristics between the cellular product used in the animal studies 
and the product proposed for clinical use should be thoroughly described in the study 
report. 
 
B.  Model Selection and Data Reports 
 
1.  Use of In Vitro Data 
 
In vitro data, i.e., immunophenotype or functional assays, can be used to make 
inferences about the potential activities of these cellular products.  This information 
may in turn be used to direct the design and extent of the bench and animal testing 
needed to support a clinical trial.  
 
2.  Small Animal Models 
 
Small animal models (e.g., immunodeficient or immunocompromised rodents) can 
provide information regarding the ability of the human cellular product to target the 
myocardium, as well as insight into potential safety issues related to the administered 
cells.  These models can be used to study the potential for cellular products to survive 
and differentiate in the myocardium following infarction.  However, they do not lend 
themselves to sensitive assessment of overall cardiac function or adverse findings 
related to catheter administration of cellular products due to constraints of anatomy 
and physiology related mainly to body size. 
 
5  Contains Nonbinding Recommendations 
 
3.  Large Animal Models 
 
Large animal models (e.g., pigs, sheep, and dogs) can provide information on the 
safety and activity of cellular products and the delivery systems, leading to the 
selection of a potentially safe starting dose for a Phase 1 clinical trial.  In addition, 
these models can be used to address issues such as cell number, volume, rate of 
injection, and the optimal location for product administration.  These data cannot be 
generated using small animal models due to the inability to directly test catheters for 
clinical use and the limited ability to monitor cardiac function.  
 
Large animal models of ischemia can be used to evaluate the activity and safety of 
cellular products following myocardial infarction.  Models for non-ischemic 
congestive heart failure are more limited.  Pathologies resulting from the commonly 
used methods for inducing cardiac ischemia (ligation, ameroid constriction and bead 
embolization) are not fully representative of the predominant mechanism of ischemia 
in humans, atherosclerotic coronary heart disease with vessel narrowing and collateral 
formation.  However, these procedures are useful for modeling acute, subacute and 
chronic myocardial infarction in animals because they allow assessment of cellular 
products in ischemic microenvironments and ischemia-damaged tissues. 
Intramyocardial injection of cellular products may necessitate additional animal 
studies to explore factors contributing to the development of arrhythmias.  These 
factors may include the composition of the cellular product, the dose of cells 
(absolute cell number and volume), and the site of cell implantation (with respect to 
anatomic features such as major conduction pathways or valves and to location within 
a scarred, ischemic area of myocardium). 
 
4. Study  Duration 
 
The preclinical data package should include studies of sufficient duration to 
adequately monitor for potential acute and/or chronic adverse findings that have 
either a rapid or delayed onset.  It is essential to assess chronic adverse findings 
which may be due to growth and remodeling of the cellular product within the cardiac 
wall.  
 
5.  Animal Report(s) to be Submitted in the IND 
 
You should provide adequate information on any animal studies conducted using the 
investigational product, whether adverse or supportive, relevant to the evaluation of 
the safety of the investigational product.  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, you must provide a brief statement of the 
reason for the non-compliance (21 CFR 312.23(a)(8)(iii)) and you should specify any 
6  Contains Nonbinding Recommendations 
 
areas that deviate from the prospectively designed protocol and the potential impact 
of these deviations on study integrity.   
 
For each preclinical report, you should describe the purpose of the study and provide 
a detailed methods section that includes information on the creation and location of 
the cardiac defect.  Reports should include standard assessments as well as 
evaluations of pathological, histological, electrophysiological, and cardiac function. 
 
C.  Leveraging Data 
 
The amount, quality, and applicability of existing data (preclinical and clinical) for the 
cellular product, route of administration, and trial design that you intend to employ are 
factors that can influence the scope of the preclinical testing program.  We recommend 
that you design your preclinical testing program 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. 3) and any subsequent 
guidances that address the preclinical testing paradigms issued by CBER.  Ultimately, the 
choice of the particular model(s) and overall preclinical study design should reflect the 
intended clinical situation.  Early consultation with FDA to discuss applicability of a 
particular experimental approach prior to its implementation can be helpful.  Additional 
information concerning the design of preclinical studies can be obtained from the March 
18-19, 2004, Cellular, Tissue and Gene Therapies Advisory Committee (formerly named 
the Biological Response Modifiers Advisory Committee) meeting minutes.3  
 
 
V.  DELIVERY SYSTEM EVALUATION AND TESTING 
 
The following sections describe the information that should be included in your IND to fully 
characterize the identity and performance of an intravascular catheter delivery system.  Any 
other associated delivery methods, such as direct injection, should be fully described within the 
clinical protocol.     
 
A.  Regulatory Considerations 
 
1.  Master Files 
 
If you plan to rely on data that concerns the performance of your delivery system and 
that is owned by another entity and contained in an IND, investigational device 
exemption (IDE), or master file, you must obtain and include in your submission a 
signed letter of cross reference stating that FDA has permission to access this 
information (21 CFR 312.23(b)).  This letter also should state the location of this 
information within the file.  You also should provide a scientific rationale that clearly 
explains why the leveraged data supports the performance of your delivery system 
                                                 
 
3 The meeting minutes are available on the FDAs website at 
http://www.fda.gov/ohrms/dockets/ac/cber04.html#BiologicalResponseModifiers (Accessed Aug. 23, 2010). 
7  Contains Nonbinding Recommendations 
 
and why any differences in evaluation conditions between the leveraged data and 
your proposed study do not affect the applicability of the leveraged data to the 
proposed study. 
 
2.  Identification 
 
We recommend that you identify in your clinical protocol the device manufacturer, 
models, regulatory status, and sizes of the catheters to be used in your study.  
Additionally, we recommend that you include a description of the catheter design 
requirements and a complete materials list.   
 
3. Prior  Information 
 
Safety information regarding the use of your delivery system (including its use in 
situations similar to those in the current application) in the United States or abroad 
should be included.  Safety information may be obtained from studies that you have 
conducted or from the literature.  Safety information may also be contained in other 
files (e.g., INDs, IDEs, Premarket Approvals, 510(k) premarket notifications, master 
files, etc.) for which you have obtained a letter of cross reference. 
 
4. Risk  Analysis 
 
You should provide in your IND a scientific rationale, incorporating available 
preclinical and clinical data, which demonstrates that the use of your delivery system 
does not constitute an undue risk to the patient.  This rationale should include a risk 
analysis based on the design and intended use of the delivery system that assesses the 
risks posed to the patient by the delivery system.  For each risk, you should describe 
what measures, if any, you have taken or will take to mitigate that risk.  
 
B.  Preclinical Testing of the Delivery System 
 
We recommend that you evaluate the performance of your delivery system using a 
battery of in vitro and in vivo tests.  Testing should demonstrate that the delivery system 
is capable of safely delivering the cellular product according to the specifications 
provided in the clinical protocol.  Your preclinical test regimen should incorporate the 
following recommendations. 
 
1. Test  Conditions 
 
Any testing should simulate the clinical delivery procedure as closely as possible and 
should evaluate the full range of delivery systems used in the study.  For variables 
such as product concentration and/or volume, delivery pressure/flow rate, and the 
number of delivery steps, worst case testing (to assess how the variables being tested 
are affected by worst-case clinical conditions that may be encountered in the clinical 
trial) should also be conducted, unless there is justification for not performing the 
testing.   
8  Contains Nonbinding Recommendations 
 
 
2. Data  Reporting 
 
When describing the preclinical tests, you should provide the following information.  
 
  a description of the test protocol; 
  the number and sizes of the samples tested; 
  the acceptance criteria, including the clinical relevance of the criteria; 
  the test results, including average values and data ranges; and 
  the conclusions you drew from the test results. 
 
3.  In Vitro Testing 
 
We recommend that you evaluate the mechanical performance of the delivery system 
using in vitro models to ensure that the delivery system can safely and effectively 
deliver biological products.  Typically, in vitro testing establishes the performance 
limits of the delivery system.  As such, satisfactory in vivo data does not necessarily 
obviate the need for in vitro testing.  
 
Currently, the scientific literature demonstrates the feasibility of two concepts for 
catheter based delivery of cellular products: 
 
  infusion of cell suspensions into the coronary vasculature that supplies the target 
region of myocardium; and 
  injection of cell suspensions directly into the target region of myocardium using 
catheters that contain injection needles. 
 
Other concepts for catheter delivery of cellular therapies may be feasible.  Since 
delivery systems can involve various principles of operation, your risk analysis 
should explain in detail why the preclinical test regimens selected are applicable to 
your delivery system, and that these tests are sufficient to assess the preclinical 
performance of the device.  You may wish to consult with FDA concerning the 
relevant performance tests for your device.  Please see the Appendix for additional 
information concerning in vitro testing of your delivery device.   
 
4.  Delivery System-Patient Biocompatibility 
 
We recommend that you demonstrate that the patient-contacting materials of the 
delivery system do not provoke a harmful biological response.  To assess the risks 
related to the materials used in the construction, processing, and storage of the 
delivery system, we recommend that you consult the FDA guidance document 
entitled Required Biocompatibility Training and Toxicology Profiles for Evaluation 
of Medical Devices, Blue Book Memo, G95-1 (Ref. 4).  In addition to the guidelines 
provided, we recommend that you evaluate the materials-mediated pyrogenicity of 
the delivery system, or explain why such evaluation is not necessary. 
 
9  Contains Nonbinding Recommendations 
 
5.  Delivery System-Product Biocompatibility 
 
To demonstrate that the delivery system can deliver the cellular product without 
damage to either the delivery system or the product, you should evaluate cell 
viability/activity, cell adhesion to the device, and device integrity using an in vitro 
model that accurately mimics the clinical protocol.  Because biologics can aggregate 
and adhere more easily at low flow rates, the worst-case delivery rate for this test may 
differ from that used in the other preclinical tests.  Further, because cellular products 
can possess extremely variable sensitivities to physical and chemical stimuli, you 
should repeat these tests for each new delivery system-product combination.  If you 
plan to leverage compatibility data which uses a different delivery system-product 
combination, you should provide a detailed and specific scientific rationale for the 
applicability of this data. 
 
6.  Preclinical In Vivo Studies 
 
Please see discussion of recommended animal models for preclinical testing of the 
study product and its delivery system under Section IV above. 
 
7. Steriliz ation  
 
FDA recommends that you provide sterilization information in accordance with the 
CDRH guidance entitled Updated 510(k) Sterility Review Guidance K90-1; Final 
Guidance for Industry and FDA, dated August 2002 (Ref. 5).  You should sterilize 
the device to a sterility assurance level of 1 x 10-6 using a sterilization cycle that has 
been validated in accordance with the quality systems regulations (21 CFR Part 820).  
 
We recommend you test the devices for pyrogenicity.  We also recommend that you 
provide the following: 
 
  description of the method used to make the determination, e.g., limulus 
amebocyte lysate; 
  identification of the testing endpoint reached and rationale for selecting that 
endpoint;  
  description of the extraction technique used to obtain the test fluid from the test 
device, showing that all clinically relevant contact surfaces of the test device were 
assessed; and 
  identification of the reference method used, e.g., ANSI/AAMI ST72 or FDA 
guidance. 
 
8.  Shelf Life  
 
FDA recommends that shelf life testing address package integrity to ensure sterility, 
as well as stable device functionality over the expected life cycle.  To evaluate device 
functionality, we recommend that you assess each of the bench tests described in the 
10  Contains Nonbinding Recommendations 
 
Appendix and repeat all tests that evaluate design characteristics affected by aging.  
We also recommend that you provide the protocol used for your shelf life testing, the 
results of the testing, and the conclusions drawn from your results. 
 
C.   Catheter Labeling 
 
You should submit clear and concise instructions that delineate the technological features 
of the specific device and how the device is to be used.  Instructions should encourage 
local/institutional training programs designed to familiarize users with the features of the 
device and with its safe and effective use. 
 
 
VI.  CLINICAL TRIAL DESIGN 
 
Standard elements of clinical trial design include patient selection, product administration, safety 
monitoring, and the choice of appropriate endpoints and control populations.  Although the trial 
design elements discussed in the following sections of the guidance are intended to be applicable 
to early phase clinical trials, specific comments that pertain to Phase 3 trials also have been 
included.  Prior to submission of an IND for a pivotal trial, it is highly recommended that there 
be an active dialogue between the sponsor and FDA and that a Special Protocol Assessment 
(SPA) be submitted.  An overall development program should also include clearly defined 
criteria concerning the type and level of product activity that will lead to further development.  
When designing a clinical trial, the products mechanism of action, as well as any additional 
information that may be learned concerning the mechanism of action should also be considered.  
This may impact your selection of the primary endpoint as well as your evaluation of consistency 
among multiple endpoints.  An additional element in the use of cellular therapies, particularly 
those involving autologous products, is that the same number of a pure population of well 
characterized cells is rarely administered to each subject.  This will complicate the interpretation 
of the products activity and mechanism of action and should be considered in the trial design.   
 
A.  Subject Population 
 
1. Refractory  Angina/Ischemia 
Trials that recruit subjects with refractory angina while on optimal medical therapy 
should provide criteria for and documentation of the patients medical therapy and the 
frequency and severity of angina.  For example, the trial may require that subjects 
have a specified class of angina as defined in a standard classification (e.g., Canadian 
Cardiovascular Society class), experience a given number of angina episodes per 
week, or develop angina on exercise testing.  You may choose to have subjects 
document the number of episodes of angina per week through the use of an angina 
diary.  Criteria for optimal medical therapy should be consistent with current, 
evidence-based American College of Cardiology/American Heart Association 
(ACC/AHA) guidelines.  Documentation of the subjects response to these 
medications (angina despite the use of optimal dosing or the inability to tolerate 
certain classes or doses of anti-anginal medications, etc.) may be obtained by the use 
of a run-in period or through an accurate medical history at study entry.     
11  Contains Nonbinding Recommendations 
 
 
Trials that recruit subjects with refractory myocardial ischemia should describe the 
means of ascertaining ischemia (e.g., single photon emission computed tomography 
(SPECT) scanning or other imaging modalities).  You should document the presence 
of ischemia through the use of a standardized test (e.g., exercise tolerance test) with 
an endpoint such as the onset of electrocardiogram (EKG)-demonstrated ischemia.  
Additionally, many trials in the treatment of chronic ischemia require that subjects 
not be candidates for percutaneous or surgical coronary intervention.  This should be 
determined by an interventional cardiologist (percutaneous intervention) or a 
cardiothoracic surgeon (surgical intervention) prior to study entry.  
 
2. Acute  Ischemia/Infarction 
 
Trials that recruit subjects with acute ischemia or those in the peri-infarct period 
should employ clear definitions of these events (such as the standardized definitions 
adopted by the ACC/AHA).  The time interval between the onset of symptoms and 
product administration should be specified along with the use of background medical 
therapies that are in accordance with current ACC/AHA guidelines.  Safety should be 
a clear focus since these subjects are at high risk for additional cardiac events.  In 
these trials, you may choose to administer the study product alone (in subjects who 
are not candidates for additional intervention) or in combination with stenting, 
angioplasty, coronary bypass grafting, etc.  The indication for these interventions 
(ongoing angina, congestive heart failure) may dictate the need for additional entry 
criteria.    
 
3. Heart  Failure 
Trials that recruit subjects with symptomatic heart failure despite optimal medical 
therapy should provide criteria for and documentation of the severity of the patients 
heart failure and the medical management of this condition.  New York Heart 
Association classification is commonly used in the categorization of heart failure.  
This classification is subjective and can lead to erroneous conclusions in a small 
randomized trial.  The clinical relevance of absolute cutoff values for the cardiac 
ejection fraction at study entry is unclear.  You may therefore wish to consider the use 
of more quantitative measures such as cardiopulmonary exercise testing in 
establishing your entry requirements.  You also may want to consider entry criteria 
based on ventricular dimensions.  Criteria for optimal medical therapy should be 
consistent with current, evidence-based ACC/AHA guidelines and should be 
documented (e.g., on the case report form).      
 
4. General  Requirements 
 
You should also provide criteria for the occurrence of recent cardiac events (ST-
Elevation Myocardial Infarction (STEMI, non-STEMI)), the timing of prior cardiac 
catheterization, and the presence of co-morbid conditions which may increase patient 
risk or limit cardiac function.  In addition, trials which administer product directly 
into the myocardial wall should provide criteria for wall thickness and the presence or 
12  Contains Nonbinding Recommendations 
 
absence of scar tissue at the site of injection.  In general, wall thickness at the site(s) 
of injection should be twice the length of maximal needle deployment.  Finally, if you 
anticipate that a drug-eluting coronary stent will be implanted, you should consider 
whether the eluted drug(s) could negatively impact the viability and activity of the 
cellular product and modify your eligibility criteria accordingly. 
 
B.  Product Administration  
 
You should provide a detailed description of product administration.  This may include: 
 
  the method used to determine the site(s) of injection, record their location(s), and to 
match the site(s) chosen with those injected; 
  the proposed number of injections (total and per cardiac wall) or the number of 
balloon inflations and their duration; 
  the concentration, volume (total and per injection), and flow rate of the cellular 
product; and 
  the method of product delivery, either through direct injection or through the use of a 
delivery device.  If a delivery device is used, detailed information concerning its 
delivery and retrieval from the site of injection should be provided.  
 
Product administration may be documented through the use of anatomic drawings, 
written descriptions, or films of the injection procedure during catheterization.  
 
C.  Safety Monitoring 
 
You must follow applicable reporting requirements outlined in 21 CFR 312.32 for 
adverse experiences associated with the use of the product.  Additional information 
concerning good clinical practice can be found in the FDA guidance entitled Guidance 
for Industry:  ICH E6 Good Clinical Practice:  Consolidated Guidance dated April 1996 
(Ref. 6).  You should record and report to FDA all procedure-related and biologic-related 
adverse experiences, including both immediate and long-term adverse experiences.  
Long-term complications of particular interest include death, arrhythmias, neurological 
events, and adverse experiences thought (mechanistically) to be associated with the 
biologic product.  You should prospectively define these adverse experiences and include 
them in the trial protocol to guide investigators, monitors, and clinical events committees. 
 
1. Cardiac  Markers 
 
We recommend that cardiac markers be obtained pre-procedure and that serial 
determinations be obtained following the procedure in all subjects.  There is no 
accepted consensus concerning the level of cardiac markers that is indicative of a 
clinically important event following an interventional procedure.  You should, 
therefore, monitor cardiac markers and include them in your study-stopping rules.  
 
 
13  Contains Nonbinding Recommendations 
 
2.  Arryhthmias and Conduction Abnormalities 
 
The cardiac rhythm should be monitored during the procedure and subjects should be 
placed on telemetry following the procedure.  In addition, serial EKGs should be 
performed.  In reporting these arrhythmias, a distinction should be made between 
isolated ventricular ectopy during product administration and more complex or 
sustained arrhythmias.  At each clinical visit, you should focus on a history of 
palpitations, chest pain, dyspnea, fatigue, lightheadedness, or syncope in an effort to 
identify subjects with arrhythmia.  Holter monitoring (or a similar system) should be 
considered in all subjects.  If episodes are infrequent, an event recorder, which allows 
the patient to transmit the EKG to a recording facility when the arrhythmia occurs, 
may be more useful.  Special attention should be given to subjects receiving skeletal 
or cardiac myoblasts.  These subjects should undergo serial monitoring of their 
cardiac rhythm (e.g., with a Holter monitor) regardless of symptoms.  Consideration 
should also be given to the placement, prior to the administration of the cellular 
product, of an automatic implantable cardioverter-defibrillator in subjects who may 
be at increased risk of experiencing arrhythmias due to the cellular therapy or the 
procedure used to administer the cells. 
 
3.  Myocardial Perforation/Pericardial Effusion 
 
To monitor for the development of a pericardial effusion following product 
administration, you should perform post-procedural echocardiography (or another 
study capable of detecting a pericardial effusion) in subjects undergoing injection of 
the cellular product into the cardiac wall.  These studies should be obtained 
immediately following the procedure and then at 4 to 6 hours post procedure.  
Abnormal findings should be followed to resolution.  
 
4.  Unique Monitoring Requirements 
 
Cellular therapies may include the administration of autologous or allogeneic cells.  
You should monitor subjects receiving allogeneic cells for the development of a 
cellular and a humoral immune response.  It may take several weeks for the host to 
develop an immune response to allogeneic cells.  Further, these cells may grow and 
differentiate within the host resulting in a change in the level or expression of cell 
surface markers and altering the immune response.  The timing of the blood samples 
to assess this response is critical.  In addition to laboratory testing, subjects should be 
monitored for the development of a clinical immune response.  An additional 
consideration is those subjects who may require a future cardiac transplantation.  
Allogeneic cells should be used with caution in these subjects since they may 
sensitize them to additional human antigens.     
 
5. Stopping  Rules 
 
We recommend that all protocols for the use of cellular therapies in the treatment of 
cardiac disease contain stopping rules.  These stopping rules should address the 
14  Contains Nonbinding Recommendations 
 
considerations discussed in this section (i.e., safety monitoring), as well as those 
issues unique to the product and its method of delivery.   
 
6.  Duration of Follow-Up 
 
Since the purported mechanism of action of these products involves tissue remodeling 
and integration, long-term follow-up is essential.  Long-term follow-up should 
include both the evaluation of late adverse events and the persistent activity of the 
product.  The establishment of long-term activity is fundamental to the assessment of 
the risk-benefit ratio.  The timing of endpoint assessment and the duration of follow-
up may vary with the product and its indication.  In many instances, the long-term 
outcome should be assessed prior to product approval while in other instances, 
additional information concerning long-term outcome may be submitted following 
licensure.  You should provide a long-term follow-up plan within the protocol. 
 
D.  Study Endpoints 
 
You should carefully consider the products expected mechanism of action and the 
indication you are seeking in your choice of study endpoint(s).  In early phase clinical 
trials, you may wish to examine a small number of endpoints.  This will allow you to 
evaluate various methods of assessment and to determine the degree of variability in the 
study product and in this endpoint.  The insight that you gain from early phase clinical 
studies should help guide the selection of a primary endpoint for a Phase 3 study.  For 
Phase 3 studies, the primary endpoint should reflect the clinically relevant effect of your 
product.4  In Phase 3 or in earlier studies, you may wish to utilize one or more of the 
following: (1) an evaluator who is independent of the study team; (2) a clinical events 
adjudication committee; or (3) a core laboratory.  Further information may be obtained 
from the FDA guidance entitled Guidance for Industry:  Providing Clinical Evidence of 
Effectiveness for Human Drugs and Biological Products dated May 1998 (Ref. 7). 
 
1. Refractory  Angina/Ischemia 
 
You should carefully consider the indication for use in seeking a claim for the 
treatment of refractory chronic angina/ischemia.  For example, if you intend to pursue 
an indication for increasing exercise tolerance in patients with chronic angina, 
exercise duration as measured by exercise tolerance testing could be used as the 
primary efficacy endpoint.  However, exercise tolerance testing should also examine 
the time to 1 mm ST depression, which may be indicative of an anti-ischemic 
mechanism of action.  Subjective measurements such as the time to the onset of 
angina during exercise testing may also provide supportive data.  Additional 
endpoints that may be of value in a blinded study include, but are not limited to, 
Canadian Cardiovascular Society angina class, and angina frequency as recorded in 
                                                 
 
4
For more information, please refer to the guidance International Conference on Harmonization E8: 
General Considerations for Clinical Trials, December 1997 (Ref. 8). 
15  Contains Nonbinding Recommendations 
 
angina diaries.  You may also consider the use of secondary endpoints such as change 
in SPECT imaging or echo wall motion scores. 
 
2. Acute  Ischemia/Infarction 
 
Trials designed to test the products effect on acute myocardial ischemia or the return 
of function post myocardial infarction may consider endpoints such as mortality or 
number of subsequent cardiovascular hospitalizations.  You may also consider the use 
of secondary endpoints such as change in single photon emission computed 
tomography imaging, echo wall motion scores, or infarct size.  Additional secondary 
endpoints which may be of value in a blinded study include, but are not limited to 
New York Heart Association class, Canadian Cardiovascular Society angina class, 
and angina diaries.  With each of these endpoints, you should consider the 
contribution of early death to the analysis of this endpoint and to the number of 
subjects enrolled in your study.  When selecting an endpoint for use in these studies, 
you should also consider the relative contribution of additional interventions (e.g., 
stent placement, bypass grafting) to patient outcome. 
 
3. Heart  Failure 
 
Trials designed to test the products effect on heart failure may consider endpoints 
such as mortality, the number of subsequent cardiovascular hospitalizations, 
cardiopulmonary exercise testing, six minute walk, change in ejection fraction, and 
the need for various interventions (e.g., an implantable defibrillator, left ventricular 
assist device, transplantation).  Additional endpoints which may be of value in a 
blinded study include, but are not limited to, New York Heart Association class or 
validated patient reported outcome questionnaires.  In general, Phase 3 studies should 
use endpoints such as mortality and cardiovascular or heart failure hospitalizations, 
whereas endpoints, such as ejection fraction, that have not been validated as 
surrogates for clinical outcome are not considered to be acceptable as primary 
efficacy endpoints for pivotal trials.  Each of these endpoints should be carefully 
considered in terms of the long- and short-term risk-benefit ratio of the product.  You 
may also consider the use of secondary endpoints such as change in left ventricular 
mass and left ventricular dimensions which are suggestive of reverse remodeling.   
 
4.  Unique Endpoint Considerations 
 
Elements unique to the design of clinical trials involving cellular therapies include the 
duration of follow up and the effect of product variability on outcome.  The need for 
tissue remodeling and integration with many of these products suggests that optimal 
function may be obtained many months after product administration.  This should be 
assessed during early phase clinical trials and considered in the timing of endpoint 
assessment in Phase 3 studies.  The need to demonstrate long-term outcome should 
also be considered.  To adequately assess the risk-benefit ratio of these products, all 
studies of cellular therapy in cardiac disease should, in general, follow subjects for 
survival. 
16  Contains Nonbinding Recommendations 
 
 
Cellular therapies, particularly those involving an autologous product, rarely 
administer the same number of a pure population of well characterized cells to each 
subject.  Therefore, early phase clinical trials should be designed to assess the level of 
variability in product manufacture and to examine subject response in terms of the 
number, type, and location of the administered cells.  In many instances, too few 
subjects will be available in each group.  One possibility is the use of preclinical 
models to identify the parameters that are essential to the activity of the product and 
to address these issues in early phase clinical trials.  For Phase 3 trials, interpretation 
of outcome data depends upon accurate assessment of variability in the treatment 
effect.  
 
E.  Choice of Control 
 
Trials for the treatment of cardiac disease have the potential for bias, including positive 
and negative placebo effects, treatment bias, and assessment bias.  Because of this, 
randomization of subjects to an active treatment arm or to a well-constructed control arm 
is one of the most important issues in trial design.  The choice of controls will determine 
product labeling, sample size, the hypothesis tested (e.g., superiority versus non-
inferiority), and the study endpoint(s)).  In general, the control group should receive the 
current standard of care in a particular disease setting.  The experimental therapy may 
then be compared to the standard of care or used in an add on design in which subjects 
receive standard treatment with or without the experimental therapy.  A detailed 
discussion on this is available in the Guidance for Industry:  ICH E10 Choice of Control 
Group and Related Issues in Clinical Trials dated May 2001(Ref. 9). 
 
While control arms are essential in Phase 3 trials, the use of a control arm also may be 
considered to facilitate the assessment of product safety and/or activity in early phase 
clinical trials.   
 
1.  Controls for Surgical Administration 
 
In general, unless there is minimal risk to the subject, we do not recommend that a 
surgical procedure be performed solely for the placement of cellular therapy.  
However, an add on design in which cellular therapy is administered at the time of 
the surgical procedure and the blind maintained by use of placebo injections or a 
separate team to perform post-procedure patient care and endpoint assessment may be 
acceptable. 
 
2.  Controls for Percutaneous Administration 
 
If a percutaneous procedure, transendomyocardial or intracoronary administration 
with balloon inflation is performed solely for the delivery of cellular therapy, the risk-
benefit ratio of this procedure should be carefully considered.  Depending on the risk 
involved, you may consider incorporating a control procedure into your trial.  An 
example of such a control procedure is the use of sham cardiac catheterization in 
17  Contains Nonbinding Recommendations 
 
which control subjects undergo femoral artery access and the catheter is positioned in 
the aorta or left ventricle while the staff performs activities similar to those in the 
active arm.   
 
A trial design that includes a sham control may permit the differentiation 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 is most important for 
studies with subjective endpoints such as reduction in patient-reported symptoms.  
Sham surgical procedures/treatments involve more risk than would be expected to 
occur in the placebo control arm in drug trials, but should be considered when 
inclusion of a sham study arm will facilitate the assessment of product safety and/or 
activity.  If sham surgical controls are used, the safety profile of the surgical 
procedure should be established in earlier-phase single-arm studies.  Due to the added 
risk to subjects who receive a sham procedure, you may consider designing the study 
so that the study product may be administered to control subjects after the study 
period has ended, in the event that efficacy has been conclusively demonstrated (for 
example, subjects initially randomized to receive a sham cardiac catheterization could 
subsequently receive autologous cells that were collected and frozen but were not 
administered).  In any event, all subjects in each study arm should receive standard 
medical care in accordance with good clinical practice.   
 
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.  We remind you that if a sham procedure/treatment 
is being considered in a clinical investigation involving children, the requirements of 
21 CFR Part 50 Subpart D apply.  We also remind you that if you choose a sham-
controlled trial, you should give careful consideration to maintaining the blinded 
nature of your trial for the subjects and study personnel (including evaluators of study 
assessments).  To maintain this blind, a separate assessment team may be needed to 
perform post-procedure subject care and endpoint assessment.  
 
Percutaneous administration may also be used in an add on design.  Again, the risk-
benefit ratio of the administration of the cellular product should be carefully 
evaluated and the use of various controls carefully considered.  Finally, you may wish 
to use a design in which subjects are randomized to cellular therapy or best supportive 
care.  As with sham-controlled studies, subject management and endpoint assessment 
teams that are blinded to treatment allocation may be needed. 
 
F.  Informed Consent in Trials Involving Long-term Follow-up Observations 
 
Long-term follow-up observations will help to fully assess the results of tissue integration 
and differentiation of the cellular product.  This allows the collection of, as yet, 
uncharacterized late adverse experiences and provides an assessment of product risk (and 
the risk of product administration) in terms of persistent benefit.  In general, long-term 
follow-up observations should be built into all phases of these trials.  
18  Contains Nonbinding Recommendations 
 
 
The informed consent document must describe, among other things, the purposes of the 
research and the expected duration of the subjects participation and the procedures to be 
followed (21 CFR 50.25(a)(1)).  Accordingly, the informed consent document must 
explain the purpose and duration of long-term follow-up observations, including the time 
intervals and location/method of subject contact (21 CFR 50.25).   
 
G.  Statistical Considerations 
 
For Phase 3 studies, the statistical analysis plan should clearly define the primary 
endpoint, the primary analysis population, and the test statistic that will be used to 
analyze the primary endpoint.  In general, the primary efficacy analysis should be 
conducted in the intent-to-treat population.  The method that will be used to handle 
missing data in this analysis should be pre-specified.  If missing data are imputed, this 
should be supported by a series of sensitivity analyses in which a variety of imputation 
methods are used, including a worst case scenario.  In trials for indications that are likely 
to have a high mortality rate (e.g., trials that involve subjects with acute myocardial 
infarction), you should also pre-specify the statistical handling of subjects who die before 
the time of efficacy endpoint assessment.  (Note:  a large amount of missing data may 
make the results of any trial difficult to interpret)   
 
It is essential that your statistical analysis plan address each of the relevant elements, 
eligibility, administration, safety monitoring, and endpoint assessment discussed in 
Section VI.  For example, you may wish to stratify by key inclusion criteria or by 
variables such as the investigator performing the procedure.  You should also include 
analyses of variability in the product and its site(s) of implantation as exploratory 
analyses in your statistical analysis plan.  Inconsistencies in endpoint assessment may be 
minimized by performing serial measurements (e.g., exercise tolerance tests performed at 
multiple time points).  Finally, given the impact that bias may have on the interpretation 
of these studies, assessments should be performed to try to identify potential sources of 
bias (e.g., unmasking of subjects, evaluators, or both, during the trial), and this 
information should be utilized in an exploratory analysis of your primary, and perhaps 
key secondary, endpoints.  
 
The primary safety analysis should be conducted in all subjects who underwent a study 
procedure whether or not they received study product.  Additional analyses may be 
necessary in all subjects who received study product.  You may also wish to include 
analyses of adverse events thought to be related to the procedure and adverse events 
thought to be related to the cellular product.  Your proposal for these analyses should be 
provided in your statistical analysis plan.  
 
If you wish to use secondary endpoints as the basis for labeling claims, note that the 
primary endpoint must first be met and also that the method of analysis for the secondary 
endpoints, along with an appropriate plan for alpha spending, should be clearly pre-
specified in the statistical analysis plan.  Please note that the findings from the primary 
analysis, all secondary analyses, and all safety analyses, as well as all exploratory 
19  Contains Nonbinding Recommendations 
 
analyses will be examined in determining the suitability of a product for licensure.  The 
Guidance for Industry:  ICH E9 Statistical Principles for Clinical Trials dated 
September 1998 (Ref. 10), provides an extensive discussion on statistical considerations 
for the design and analysis of clinical trials.  We also recommend that you interact with 
FDA early in the trial design process to collaborate on an analysis plan. 
 
 
20  Contains Nonbinding Recommendations 
 
VII.  REFERENCES 
 
1)  Guidance for Industry and FDA Staff:  Early Development Considerations for Innovative 
Combination Products (September 2006), 
http://www.fda.gov/regulatoryinformation/guidances/ucm126050.htm, accessed Aug. 23, 
2010. 
2)  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/GuidanceComplianceRegulatoryInformatio
n/Guidances/Xenotransplantation/ucm074131.htm, accessed Aug. 23, 2010. 
3)  Guidance for Industry:  Guidance for Human Somatic Cell Therapy and Gene Therapy 
(March 1998), 
http://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/g
uidances/cellularandgenetherapy/ucm072987.htm, accessed Aug. 23, 2010. 
4)  Guidance for Industry:  Required Biocompatibility Training and Toxicology Profiles for 
Evaluation of Medical Devices, Blue Book Memo, G95-1, (May 1995), 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocument
s/ucm080735.htm, accessed Aug. 23, 2010. 
5)  Final Guidance for Industry and FDA:  Updated 510(k) Sterility Review Guidance K90-
1, (August 2002), 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidanc
eDocuments/ucm072790.pdf, accessed Aug. 23, 2010. 
6)   Guidance for Industry:  ICH E6 Good Clinical Practice:  Consolidated Guidance (April 
1996),   
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm073122.pdf, accessed Aug. 23, 2010. 
7)  Guidance for Industry:  Providing Clinical Evidence of Effectiveness for Human Drugs 
and Biological Products (May 1998), 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/ucm078749.pdf, accessed Aug. 23, 2010. 
8)  Guidance for Industry:  ICH E8: General Considerations for Clinical Trials (December 
1997)  
9)  Guidance for Industry:  ICH E10 Choice of Control Group and Related Issues in Clinical 
Trials (May 2001), 
http://www.fda.gov/RegulatoryInformation/Guidances/ucm125802.htm, accessed Aug. 
23, 2010. 
10)  Guidance for Industry:  ICH E9 Statistical Principles for Clinical Trials (September 
1998), 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/ucm073137.pdf, accessed Aug. 23, 2010. 
 
21  Contains Nonbinding Recommendations 
 
 
APPENDIX:  In Vitro Testing of the Delivery Device
 
Since some polymers may soften at body temperature, we recommend that you perform in vitro 
testing under conditions simulating clinical use.  For example, prior to evaluation of each 
parameter, you should submerge the catheter in a saline bath at 37C for a duration consistent 
with the intended use, or pass the catheter through a U-shaped tube to simulate tracking over the 
aortic arch or other severe bend.  As part of your test report, you should describe the rationale for 
your choice of the vascular model and the effects of the model dimensions.  Additionally, you 
should include a schematic, drawing, and/or photograph of the test apparatus. 
 
Your preclinical test regimen should assess the following characteristics using a clinically 
relevant in vitro model.  Not all of these performance characteristics may be applicable to your 
delivery system and the assessment of additional performance characteristics may be appropriate. 
 
Dimensional verification:  You should ensure that the device dimensions meet specifications 
previously determined to ensure acceptable performance.  Key device dimensions may include 
the catheter length and profile, the length and diameter of injection needles, and the length of 
balloon components. 
 
Burst pressure:  The catheter body should be designed to withstand pressures typically needed to 
achieve media flow rates used in clinical practice.  You should determine the pressure beyond 
which the device is expected to leak or rupture.  You should also describe the mode(s) by which 
the delivery system fails at the specified pressure, such as rupture of the delivery shaft or leakage 
of specific seals. 
 
Flow rate:  The catheter should be designed to achieve clinically acceptable media flow rates.  
We recommend that testing be done at maximum catheter burst pressures (as identified in the test 
described above), as well as pressures typical of clinical use.  We recommend that you report the 
maximum flow rate in the device labeling.  We also recommend that you provide the clinical 
basis for your acceptance criteria. 
 
Bond Strength: 
  Tensile/bending strength:  You should characterize the resistance of your delivery system 
to tensile (pulling) and bending (flexion) forces.  You should test the bond strength at any 
location where adhesives, thermal fusion, or other joining methods are used for bonding 
sub-components of the device.   
 
  Torsional strength:  You should characterize the resistance of your delivery system to 
torsional (twisting) forces.  You should test the bond strength at any location where 
adhesives, thermal fusion, or other joining methods are used for bonding components of 
the device.  We recommend that you report the number of rotations to failure and the 
failure mode for each sample tested.  Additionally, we recommend that you report the 
number of turns to failure in the device labeling. 
 
Fatigue:  You should ensure that the delivery system can repeatedly deliver accurate quantities of 
cellular product without degradation of performance or structural damage.  You should base the 
22  Contains Nonbinding Recommendations 
 
number of fatigue cycles on the number expected clinically, plus an appropriate safety margin.  
If your device incorporates a retractable tip, you should ensure that the tip can be extended and 
retracted without failure to the clinically anticipated number of cycles, plus an appropriate safety 
margin.  Additionally, you should conduct this test in both deflected (where applicable) and non- 
deflected states to simulate actual clinical use. 
 
Stiffness:  To assess the stiffness or flexibility of the complete device, we recommend that you 
measure the deflection of the device for a given force applied to the center point of the catheter 
shaft when the catheter is suspended between the tip and the catheter/handle junction.  We 
recommend that you measure the force required to cause a finished, undeflected catheter to 
buckle.  The buckling force should not be so large that your delivery system presents a high risk 
of vessel perforation or dissection. 
 
Radiopacity:  We recommend that you determine the ability of the operator to observe the device 
using fluoroscopy or other imaging modalities.   
 
For Deflectable Catheters: 
  Steering and Deflection Cycle Test:  For devices designed to be deflected to aid with 
steering through the vasculature, we recommend that you demonstrate that the catheter 
can withstand a clinically relevant number of complete actuations of the deflection 
mechanism without failure, plus an appropriate safety margin. 
  Deflection Force Test:  For devices designed to be deflected during use, you should 
measure the applied force on the distal tip when the device is deflected to 90o during full 
actuation of the deflection mechanism in the absence of any other catheter movement.  
You should explain how you constrained the catheter during this test, and why this 
method was appropriate. 
  Applied Force:  For devices designed to be deflected, we recommend that you compute 
statistics for the applied force on the distal tip from the 90o position, both during full 
actuation of the deflection mechanism without translation (tracking or retrieval), and also 
as a result of translation of the catheter without further deflection, for the various curve 
configurations.   
 
Cable/Connector Separation Test:  If operation of your device requires mechanical or electrical 
connections to accessory devices, we recommend that you determine the reliability of the 
connection between the device proximal connectors for each connector type.  This test should be 
performed by developing a test protocol that simulates device use and then testing to ensure that 
the connectors remain connected during normal use. 
 
Balloon Performance: 
 
If your device incorporates one or more balloon components, you should ensure that the balloon 
can be used safely and according to device specifications.  Depending on the design of your 
device, the following balloon performance characteristics may be applicable. 
  Balloon fatigue  You should ensure that the balloon can be repeatedly inflated and 
deflated without malfunction or structural damage.  The number of fatigue cycles should 
be based on the number expected clinically, plus an appropriate safety margin. 
23  Contains Nonbinding Recommendations 
 
  Balloon inflation/deflation time  You should ensure that the balloon can be inflated and 
deflated within clinically acceptable time frames. 
  Balloon burst  You should determine the inflation pressure or volume at which the 
balloon is expected to leak or rupture. 
  Balloon compliance  You should characterize the extent of inflation of the balloon as a 
function of the volume or pressure used for inflation.  This information will assist the 
operator in determining the proper degree of inflation for each patient treated.  
24