Guidance for Industry 
Chronic Cutaneous Ulcer and 
Burn Wounds  Developing 
Products for Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
 
June 2006 
Clinical/Medical 
 
   
Guidance for Industry 
Chronic Cutaneous Ulcer and Burn 
Wounds  Developing Products for 
Treatment 
 
 
Additional copies are available from: 
 
Office of Training and Communications 
Division of Drug Information, HFD-240 
Center for Drug Evaluation and Research 
Food and Drug Administration 
5600 Fishers Lane 
Rockville, MD  20857 
(Tel) 301-827-4573 
http://www.fda.gov/cder/guidance/index.htm 
or 
Office of Communication, Training, and  
Manufacturers Assistance, HFM-40  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
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(Tel) 800-835-4709 or 301-827-1800  
http://www.fda.gov/cber/guidelines.htm   
or 
Office of Communication, Education, and Radiation Programs 
Division of Small Manufacturers, International and Consumer Assistance, HFZ-220 
Center for Devices and Radiological Health 
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Rockville, MD  20850-4307  
DSMICA E-mail: dsmica@cdrh.fda.gov  
DSMICA Fax: 301-443-8818  
(Tel) Manufacturers Assistance: 800-638-2041 or 301-443-6597  
(Tel) International Staff: 301-827-3993 
http://www.fda.gov/cdrh/ggpmain.html 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
 
June 2006 
Clinical/Medical 
 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION.............................................................................................................1 
II.  INDICATION FOR USE CONSIDERATIONS............................................................2 
III.  PRECLINICAL CONSIDERATIONS...........................................................................2 
A.  Animal Wound Models..................................................................................................................2 
B.  Biodistribution and Pharmacokinetic Studies.............................................................................3 
C.  Toxicology Studies.........................................................................................................................3 
IV.  CLINICAL TRIAL DESIGN...........................................................................................5 
A.  Randomization and Stratification................................................................................................5 
B.  Comparator Arms..........................................................................................................................5 
C.  Blinding...........................................................................................................................................5 
D.  Wound Assessment and Quantification.......................................................................................6 
1. Ulcer Classification.........................................................................................................................6 
2. Wound Size.......................................................................................................................................6 
3. Infection...........................................................................................................................................7 
E.  Study Population............................................................................................................................7 
1. Chronic Cutaneous Ulcers...............................................................................................................7 
2. Burns................................................................................................................................................8 
F.  Standard Care................................................................................................................................8 
1. Standard Care Considerations for Chronic Cutaneous Ulcers.......................................................9 
a.  Debridement...........................................................................................................................10 
b.  Off-loading and compression.................................................................................................10 
c.  Maintenance of a moist wound environment..........................................................................10 
d.  Management of wound infection............................................................................................10 
e.  Nutritional support..................................................................................................................11 
2. Standard Care Considerations for Burns......................................................................................11 
G.  Efficacy Endpoints.......................................................................................................................12 
1. Improved Wound Healing..............................................................................................................12 
a.  Incidence of complete wound closure.....................................................................................12 
b.  Accelerated wound closure.....................................................................................................13 
c.  Facilitation of surgical wound closure....................................................................................13 
d.  Quality of healing (cosmesis and function)............................................................................13 
2. Improved Wound Care...................................................................................................................13 
a.  Treatment of wound infection.................................................................................................14 
b.  Debridement...........................................................................................................................14 
c.  Wound pain control................................................................................................................14 
3. Temporary Dressings.....................................................................................................................14 
4. Other Wound Care Claims.............................................................................................................15 
H.  Safety Considerations..................................................................................................................15 
1. Immune Reactions..........................................................................................................................15 
2. Trial Stopping Rules......................................................................................................................15 
3. Discontinuation of Treatment........................................................................................................15 
i   
4. Absorption Studies.........................................................................................................................16 
5. Irritation and Contact Sensitization...............................................................................................16 
I.  Statistical Considerations Specific for Wound-Treatment Product Trials............................16 
1. Significance Tests..........................................................................................................................16 
2. Data Transformation and Covariate Analyses..............................................................................17 
V.  WOUND-TREATMENT PRODUCT QUALITY MICROBIOLOGY.....................17 
ii  Contains Nonbinding Recommendations 
 
1
Guidance for Industry
Chronic Cutaneous Ulcer and Burn Wounds  Developing 
Products for Treatment 
 
 
 
 
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 FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
 
I.  INTRODUCTION  
 
The purpose of this guidance is to provide recommendations to sponsors for the development of 
drugs, biological products, and devices2 to treat chronic cutaneous ulcer and burn wounds (i.e., 
wound-treatment products).  The first part of this guidance addresses specific preclinical 
considerations.  The guidance then addresses important considerations in clinical study design, 
including endpoint selection and manufacturing.   
 
This guidance specifically refers to venous stasis ulcers, diabetic foot ulcers, pressure ulcers, and 
burn wounds.  For the purposes of this guidance, a chronic cutaneous ulcer is defined as a 
wound that has failed to proceed through an orderly and timely series of events to produce a 
durable structural, functional, and cosmetic closure.  A burn wound is defined as a cutaneous 
wound induced by thermal, chemical, or electrical injury. 
 
In the Food and Drug Administration (FDA), the Center for Drug Evaluation and Research 
(CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices 
and Radiological Health (CDRH) all regulate products to treat cutaneous wounds.  This guidance 
contains recommendations applicable to the development of products regulated by any of the 
three Centers.  Center-specific issues and advice are noted where appropriate.     
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
                                                 
1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER), the Center for 
Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health (CDRH) at the 
Food and Drug Administration.  
 
2 This guidance applies only to those medical devices for which clinical trials are required. 
  1 Contains Nonbinding Recommendations 
 
cited.  The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  INDICATION FOR USE CONSIDERATIONS 
 
A products labeled indication for use is based on substantial evidence and is reflective of the 
safety and efficacy of the product as determined in clinical investigations.  In the case of wound-
treatment products, the stated indication should include the types of wounds for which a product 
is intended (e.g., venous stasis ulcer, diabetic foot ulcer, pressure ulcer, burn sites, and donor 
sites) as well as the products benefits, risks, and limitations.  Because wounds differ in their 
pathophysiology, it is difficult to generalize results obtained from a trial conducted in subjects 
with one wound type to patients with another wound type.  Therefore, separate clinical trials 
should be considered for each type of wound indication sought.  However, if a scientific 
rationale and clinical data support clinical activity of a product in more than one wound type, it 
may be possible for studies performed in one wound type to support another in establishing 
substantial evidence of efficacy and safety.  
 
 
III.  PRECLINICAL CONSIDERATIONS 
 
This section consists of specific points to consider for wound indications (including wound 
healing and wound care) for drugs and biological products.  It is not intended as a general 
guidance for preclinical testing.3
 
A.  Animal Wound Models 
 
Animal wound models can be helpful in establishing pharmacological responses, as well as 
assessing potential toxicities of wound-treatment products.  The choice of an animal wound 
model should be based on the best science available, as well as its applicability to the scientific 
questions that one is attempting to answer.  The animal species selected should exhibit a 
biological responsiveness to the test product (i.e., should be a relevant species).  Although animal 
models can be useful for establishing proof of concept for some types of products, in general 
they can be inadequate predictors of efficacy in clinical trials.  Since currently there are no ideal 
animal models for chronic wounds or extensive burns, multiple animal models typically should 
be used to assess activity of wound-treatment products.  Fibroplasia and stroma formation can be 
evaluated by subcutaneous injection of some products in various animal models.  Contraction 
and re-epithelialization can be evaluated by topical application on full-thickness excisional 
                                                 
3 General guidance for preclinical testing of drugs and biologics can be found in International Conference on 
Harmonisation (ICH) documents, including M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials 
for Pharmaceuticals and S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.  We update 
guidances periodically.  To make sure you have the most recent version of a guidance, check the CDER guidance 
Web page at http://www.fda.gov/cder/guidance/index.htm. 
 
For medical devices, general guidance for assessing preclinical safety can be found in Blue Book Memorandum 
#G95-1 Use of International Standard ISO-10993, Biological Evaluation of Medical Devices Part 1: Evaluation and 
Testing.   
  2 Contains Nonbinding Recommendations 
 
wounds or in a pig graft donor site model.  Pigs can be useful models because their cutaneous 
architecture is most similar to that of human skin.  Induction of angiogenesis can be evaluated in 
chick chorioallantoic membrane or rabbit cornea.  Breaking strength can be tested in a rat linear 
incision model.   
 
In impaired-healing models, the window of time for measuring treatment effects is extended.  
Impaired-healing models include infection, necrotizing trauma, irradiation, administration of 
corticosteroids or chemotherapeutic drugs, or drug-induced or genetic diabetes mellitus in mice, 
rats, hamsters, guinea pigs, and young pigs.  Each model has one or more of the characteristics 
that can be useful for evaluating a products activity.  For example, the rabbit ear dermal ulcer 
model is useful for evaluating re-epithelialization because it lacks the vigorous wound 
contraction seen in other rodent models and, in addition, allows for the induction of ischemia in 
the wound.  There is extensive scientific literature that can be consulted for a more 
comprehensive discussion of the advantages and disadvantages of the models previously cited, in 
addition to other available wound models. 
 
B.  Biodistribution and Pharmacokinetic Studies 
 
Although there are no ideal animal models for chronic wounds, in vivo biodistribution and 
pharmacokinetic (BD/PK) studies generally provide helpful data for the design of toxicology 
studies.  Preferably, the pharmacokinetic (PK) profile can be determined in the same animal 
species that will be used in the toxicology assessment.  For topical wound-treatment products, 
application of the product to a wound site on the animals skin may provide more relevant 
information than application to intact animal skin.  When technically feasible, the potential for 
regional and systemic exposure to a product for a chronic wound indication might be better 
approximated by subcutaneous injection.  Consideration should also be given to alterations of the 
BD/PK profile and the potential for product accumulation with repeated dosing.  Information 
regarding the stability of the product at the target site (target receptor levels for biological 
products) contributes to a better understanding of the activity and potential toxicity of the 
wound-treatment product.   
 
C.  Toxicology Studies 
 
The design of nonclinical toxicology studies for wound-treatment products should reflect, as 
much as possible, the intended clinical use of the product with respect to route, dosing regimen, 
and duration of exposure.  It is important to assess any exaggerated pharmacological responses 
and potential toxicities of wound-treatment products.  Administration of the wound-treatment 
product at multiples higher than the anticipated therapeutic dose (potentially determined from 
wound models) can provide an estimate of the therapeutic index (toxic dose/effective dose) to aid 
in the selection of the initial clinical starting dose.  Vehicle and sham controls should be 
employed where appropriate to evaluate any adverse or beneficial effects of product formulation 
ingredients on wound healing and adverse events.  The vehicle control animals should receive 
the same excipients and formulation as are in the intended clinical product, without the active 
agent.  The sham control animals should be manipulated in the same manner as the vehicle 
control animals, but should not receive the vehicle or the active agent. 
 
  3 Contains Nonbinding Recommendations 
 
Cutaneous irritation and sensitization testing should be generally indicated for all topically 
applied wound-treatment products, since these adverse reactions can seriously complicate human 
wounds.  Products that will be delivered in an aerosol formulation should be evaluated for 
pulmonary toxicity, and possibly ocular toxicity (products known to be cutaneous irritants are 
assumed to be ocular irritants, and testing is generally waived).   
 
The immunogenic potential of biotechnology-derived wound-treatment products can be a 
confounding factor in repeat-dose toxicology studies because antibodies to the administered 
product may affect the PK profile, the pharmacodynamic response, and the toxicity of the 
product.  Although the development of antibodies to antigenic products generally has not been 
predictive of the clinical response, data on antibody formation should be collected to provide a 
complete preclinical safety assessment of the wound-treatment product.  Sponsors are 
encouraged to seek FDA input during development to ensure collection of adequate 
immunogenicity information. 
 
Carcinogenicity studies generally should be conducted for drugs intended to treat chronic 
ulcers.4  For biological products, the 2-year chronic bioassay and carcinogenicity study currently 
used for drugs is generally inappropriate because of species specificity and immunogenicity of 
the product.  However, data in rodent initiation-promotion carcinogenesis models support the 
potential of various growth factors to act as tumor promoters.  Current unresolved issues 
regarding the carcinogenic and tumorigenic potential of wound-treatment products include the 
likelihood of tumor promotion in the proposed patient populations and the additional 
susceptibility of patients exposed to environmental or other potential carcinogens (e.g., systemic 
chemotherapy) as well as the possibility of inducing scar carcinomas in chronic wounds.  
Sponsors are encouraged to address this issue by referencing the existing scientific literature, and 
evaluating the potential of the test product to stimulate the growth of normal and malignant cells 
that express the receptor for the product.  Sponsors are encouraged to seek FDA input for 
product-specific questions that can affect the carcinogenicity evaluation.  
 
Reproductive and developmental toxicology studies are recommended for wound-treatment 
products that might be administered to women of childbearing potential.5  
 
Genotoxicity studies should be performed for all nonbiological drug products.  These studies are 
indicated for a biotechnology-derived product only when supported by appropriate scientific 
rationale.6  
 
                                                 
4 Guidance for drug carcinogenicity studies can be found in the ICH documents S1A The Need for Long-Term 
Rodent Carcinogenicity Studies of Pharmaceuticals, S1C Dose Selection for Carcinogenicity Studies of 
Pharmaceuticals, and S1C(R) Addendum to Dose Selection for Carcinogenicity Studies of Pharmaceuticals: 
Addition of a Limit Dose and Related Notes. 
 
5 General guidance on preclinical study designs can be found in the ICH document S5A Detection of Toxicity to 
Reproduction for Medicinal Products. 
 
6 Further guidance is available in the ICH documents S2A  Specific Aspects of Regulatory Genotoxicity Tests for 
Pharmaceuticals and S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals.  The ICH 
document S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals provides further discussion 
regarding biological products. 
  4 Contains Nonbinding Recommendations 
 
 
IV.  CLINICAL TRIAL DESIGN 
 
This section consists of specific points to consider for wound indication trial design.  It is not 
intended as general guidance on trial design.7   
 
A.  Randomization and Stratification 
 
Randomization is particularly important for reducing bias in wound indication trials because 
standard wound care procedures and baseline wound characteristics generally have a profound 
effect on outcome.  If variation in standard wound care procedures among clinical study sites is 
unavoidable, stratification by study center is recommended to minimize any imbalances among 
study arms.  In some cases, it may be appropriate to prospectively stratify randomization by 
other important covariates, such as wound size or duration.  Variables thought to significantly 
affect outcome should be incorporated into the planned efficacy analyses even if these variables 
are not used for stratification in randomization (see section IV.I., Statistical Considerations 
Specific for Wound-Treatment Product Trials).  
 
B.  Comparator Arms 
 
A comparator arm is recommended for many wound-treatment product trials involving drugs, 
biologics, devices, and combination products (i.e., drug delivery studies or cellular wound 
dressings).  This is usually a vehicle control arm.  The vehicle control should contain the same 
formulation and excipients as the study product, without the active agent.  Such trials should be 
performed with identical standard-of-care procedures in both the control and investigational 
product arms.  If the effect of a products vehicle is not established, product development should 
also include a study arm treated with standard of care alone, usually in exploratory studies.  In 
the selection of comparator groups, careful consideration to optimizing the dosage, frequency of 
administration, and method of use is important.   
 
Trial designs in which subjects serve as their own control have been used to study topical 
products intended for serious burns in an attempt to minimize the heterogeneity characteristic of 
this patient population.  However, this approach compromises the evaluation of systemic 
toxicity, necessitating additional controls or studies to collect adequate safety data.   
 
C.  Blinding 
 
In general, blinding of subjects and investigators to the assigned treatment reduces bias and 
should be employed when feasible.  Early trials of topical wound-treatment products often 
include a treatment group that receives only standard care (see section IV.B., Comparator Arms) 
to establish whether the vehicle has an effect on healing.  Often the standard care only arm 
cannot be blinded.  In other cases, especially for trials of some medical devices, it is impractical 
or unethical to implement a control treatment that mimics the test product for the purposes of 
blinding.  In these situations, blinded assessment by a third-party evaluator should be considered. 
                                                 
7 General guidance on this topic can be found in the ICH documents E8 General Considerations for Clinical Trials, 
E9 Statistical Principals for Clinical Trials, and E10 Choice of Control Group and Related Issues in Clinical Trials. 
  5 Contains Nonbinding Recommendations 
 
 
D.  Wound Assessment and Quantification 
 
For most ulcer types, we encourage the selection of a single target lesion for efficacy 
determination before subject randomization.  In some cases, it may be appropriate to treat other 
lesions with the investigational product to obtain additional safety information, which is still 
reported as per patient.  An alternative approach, that may be appropriate, is complete healing of 
all lesions reported as per patient.  
 
The tools to assess clinical trial endpoints should be both prespecified and, for multicenter trials, 
standardized across clinical sites.  For example, if photographs will be used for measurement and 
documentation of wound changes, the lighting, distance, exposure, and camera type should be 
specified and consistent at all clinical centers.   
 
Regardless of the methodology, the following variables should be addressed in all clinical trials 
for wound-treatment products. 
 
1.  Ulcer Classification 
 
The type of chronic ulcer (venous stasis, diabetic, pressure, arterial insufficiency) usually can be 
determined by considering the subjects history and performing a physical examination.  
Objective tools to confirm the diagnosis can include the following:  
 
  Doppler sonography to qualify and quantify vascular insufficiency: arterial or venous 
(deep, superficial, or mixed) 
  Transcutaneous oxygen tension (t pO ) measurements 
c 2
  Ankle/brachial index 
  Filament testing to quantify sensory neuropathy 
  Measurement of laboratory markers for diabetes mellitus 
  Histopathology of ulcer biopsies to exclude neoplastic, immune-mediated, or primary 
infectious disease 
 
2.  Wound Size 
 
Quantitative measurements of wound size are routinely used to assess initial wound size before 
and after debridement, as well as progress toward closure.  For ulcers that are more superficial, 
such as venous stasis ulcers, the area of the wound opening should be measured.  For ulcers that 
extend deeply into tissue, volume or surface area should be measured when feasible.  The extent 
of tissue undermining and sinus tracts is an important part of the evaluation.  In the case of 
diabetic ulcers, qualitative assessment by determining the maximal depth is a frequently used 
method.  For other ulcers, such as pressure ulcers, molds can be used to provide precise 
measurement of volume and surface area.  Alternatively, semiquantitative measurements can be 
achieved using the maximal width/length/depth and shape coefficient.  There are also widely 
accepted criteria used to classify the stages of ulcers (e.g., National Pressure Ulcer Advisory 
Panel (NPUAP) for Pressure Ulcers: NPUAP Classification, Wagners Classification for foot 
ulcers). 
  6 Contains Nonbinding Recommendations 
 
 
For acute burns, it is important to attempt a determination of the burn depth as this parameter 
affects both the choice of standard-of-care regimen and the expected time to healing.  The 
distinction between partial, full-thickness, and indeterminate wounds is currently based on 
clinical judgment; biopsy and Doppler measurement of blood flow are sometimes used as well.  
Clinical parameters include appearance of the tissue, sensation, and bleeding upon debridement.  
Wound depth heterogeneity is often an impediment to quantitative measurement, and burn depth 
extension in the first 24 to 48 hours post-injury frequently necessitates reassessment.  Because 
burn wound depth often becomes better defined following the initial evaluation, the initial 
clinical assessment of the body surface area affected by deep partial full-thickness (2nd degree) 
and full-thickness (3rd degree) wounds can be compared with the total body surface area 
ultimately grafted.  
 
When the target wound is an autograft donor site, the protocol should clearly delineate the 
method for harvest, and the size, thickness, and anatomic location of the donor site. 
 
3.  Infection 
 
Infection should be assessed clinically by symptoms and signs that include purulent drainage, 
erythema, warmth, exudation, odor, pain, fever, and leukocytosis as well as wound size and time 
to wound healing.  Fever, pain, and leukocytosis may be absent, however, especially in subjects 
with diabetic foot ulcers.  Quantitative and qualitative culture of a tissue biopsy can be used at 
baseline to help determine if the wound is infected or merely colonized, and to guide appropriate 
antimicrobial therapy.  This method is generally preferred to quantitative and qualitative culture 
of swab specimens.8  
 
E.  Study Population 
 
The patient population to be included in clinical trials should be appropriate for the type of 
wounds to be studied.  In general, the patient population chosen should be one that optimizes the 
studys ability to detect a treatment effect, but should also be a population that reflects the 
population for which the product will be indicated and used. 
 
1.  Chronic Cutaneous Ulcers 
 
Three of the major categories of chronic cutaneous ulcers are diabetic ulcers, venous stasis 
ulcers, and pressure ulcers.  As previously stated, separate trials generally are appropriate for 
each type of chronic ulcer because these ulcers have different etiologies and potentially different 
responses to therapy.  If demonstration of efficacy is restricted to ulcers with a limited range of 
size or duration, and the ability to extrapolate to larger or more recalcitrant ulcers is unclear, then 
the labeled indication can be limited to ulcers with similar parameters to those studied.   
 
                                                 
8 In 1998, the Agency published a series of draft guidances on drugs to treat antimicrobials, including uncomplicated 
and complicated skin infections.  These guidances currently are being finalized.  Once finalized, these guidances 
will reflect the Agencys views on developing antimicrobial drug products. 
  7 Contains Nonbinding Recommendations 
 
Healing of chronic ulcers can occur as subject compliance with standard treatment improves 
during the initial involvement in a clinical trial.  Variability in aspects of care that affect outcome 
can interfere with a studys ability to demonstrate the treatment effect of the investigational 
product.  Approaches for minimizing this variability can include the use of: a) a study design 
with an initial phase (e.g., 1 to 2 weeks) when subjects receive only standard of care, and b) an 
entry criterion that excludes subjects whose study ulcer size decreases by a stated amount (e.g., 
30 percent to 50 percent) during this initial standard-of-care phase.  Thus, the randomized study 
population would exclude subjects demonstrating substantial healing resulting solely from 
improved compliance with standard care. 
 
2.  Burns 
 
The population for burn trials is usually characterized by the depth, surface area, and location of 
the burn injury, as well as subject characteristics.  Important characteristics of a burn wound 
include its cause (thermal, chemical, electrical), anatomic location, depth (full or partial 
thickness), duration, and extent (percent total body surface area).  Subject characteristics that 
affect burn wound healing include age, nutritional status, underlying medical conditions, 
concomitant injury (e.g., head trauma, inhalation injury, bone fractures), and scores that 
represent an overall severity of illness or injury (e.g., the American Society of Anesthesiologists 
(ASA) Classification, the Trauma-Injury Severity Score (TRISS), or the Acute Physiology and 
Chronic Health Evaluation (APACHE) III score).  Patients with serious burns commonly receive 
multiple concomitant treatments, making it sometimes difficult to detect a treatment effect.  For 
this reason, stratification by injury severity and other potentially confounding factors that are 
clinically significant should be considered to minimize imbalances among treatment groups.  In 
early clinical development, to protect subject safety, generally it is not advisable to include 
investigational treatment of burns in anatomic locations such as the face and hands as well as 
sites deemed high risk for developing compartment syndrome; similarly, the body surface area 
treated with the investigational product should be limited. 
 
In clinical trials of subjects with full-thickness burn wounds, donor sites for autografts are 
sometimes selected as the target wound for study.  However, the demonstration of safety and 
efficacy of a product for a donor site wound does not support the safety and efficacy of the 
product for burn wounds, because burn wounds differ in clinically significant ways from surgical 
wounds. 
 
F.  Standard Care 
 
Standard care refers to generally accepted wound care procedures, other than the investigational 
product, that will be used in the clinical trial.  Good standard care procedures in a wound-
treatment product trial are a prerequisite for assessing safety and efficacy of a product.  Since 
varying standard care procedures can confound the outcome of a clinical trial, it is generally 
advisable that all participating centers agree to use the same procedures and these procedures are 
described within the clinical protocol.  If it is not practical to apply uniform standard care 
procedures across study centers, randomization stratified by study center should be considered.  
It is also important that the sample size within study centers and wound care records be adequate 
to assess the effect of wound care variation. 
  8 Contains Nonbinding Recommendations 
 
 
A number of standard procedures for ulcer and burn care are widely accepted.  Several 
professional groups have initiated development of care guidelines for ulcers and burns.  The 
Agency does not require adherence to any specific guidelines, the basic principle being that 
standard care regimens in wound-treatment product trials should optimize conditions for healing 
and be prospectively defined in the protocol.  The rationale for the standard care chosen should 
be included in the protocol, and the study plan should be of sufficient detail for consistent and 
uniform application across study centers.  Case report forms (CRFs) should be designed such 
that, at each visit, investigators describe the type of ulcer or burn care actually delivered (e.g., 
extent of debridement, use of concomitant medications).  For outpatients, the CRF should also 
capture compliance with standard care measures, including wound dressing, off-loading, and 
appropriate supportive factors, such as dietary intake.  
 
The value of study site consistency in standard care regimens within a trial cannot be over-
emphasized because of the profound effects these procedures have on clinical outcome for burns 
and chronic wounds.  Consistency in standard care regimens is important for minimizing 
variability and allowing assessment of treatment effect.  It may be reasonable to evaluate a single 
standard care regimen in early trials to minimize this variability.  If comparison of an 
investigational product to more than one commonly used standard care option is desired, the 
overall development plan should include specific assessment of the effect of these standard care 
options on the experimental treatment.  These common options should be identified and 
addressed prospectively in clinical trial design including being clearly described in the clinical 
protocol and compliance captured via the CRFs; criteria for data poolability should be defined 
prospectively.  Every attempt should be made to minimize deviations from the procedures 
described in the protocol and subject compliance recorded in CRFs.  If more than one standard 
care regimen is used in the same clinical trial, then randomized treatment allocation within strata 
defined by these options in standard care is important. 
 
1.  Standard Care Considerations for Chronic Cutaneous Ulcers 
 
Parameters for consideration in choosing standard care procedures for chronic cutaneous ulcer 
trials include the following: 
 
  Removal of necrotic or infected tissue  
  Off-loading  
  Compression therapy for venous stasis ulcers 
  Establishment of adequate blood circulation 
  Maintenance of a moist wound environment 
  Management of wound infection 
  Wound cleansing 
  Nutritional support, including blood glucose control for subjects with diabetic ulcers 
  Bowel and bladder care for subjects with pressure ulcers at risk for contamination 
 
  9 Contains Nonbinding Recommendations 
 
a.  Debridement 
 
The presence of necrotic tissue, sinus tracts, exudation or transudation, and infection of soft and 
hard tissues can interfere with ulcer healing.  Appropriate debridement procedures for the 
indicated ulcer should be specifically defined in the protocol.  To avoid bias and confounding of 
potential treatment effects, ulcer debridement should generally precede evaluation of ulcer extent 
and infection.  Enzymatic debriding products, like other concomitant topical products, can 
confound results in topical wound-treatment product trials and generally should be avoided.  
 
The need for additional sharp surgical debridement, performed after study treatment has started, 
may indicate product-induced wound deterioration.  Any surgical debridement should be 
documented on CRFs and included in analysis of product safety and efficacy.  In general, the 
study protocol should specify that investigators discontinue study treatment if repeat 
debridement is needed to address wound deterioration.  For example, ongoing removal of callus 
as part of standard diabetic ulcer care would not require discontinuation of study treatment, but 
deep debridement for new onset osteomyelitis would.  
 
b.  Off-loading and compression 
 
Relief of pressure is critical in determining the outcome for certain chronic ulcers.  Off-loading is 
often difficult to standardize because equipment (e.g., type of bed) may not be available at all 
sites, and compliance with study procedures is labor intensive (e.g., turning).  If these critical 
aspects of effective therapeutic intervention cannot be standardized across all sites, it is 
important to specify the actual care delivered in CRFs and to consider concomitant care in the 
efficacy analyses.  For diabetic foot ulcers, compliance with off-loading is a strong factor 
associated with wound closure and should be monitored throughout the clinical trial.  Off-
loading approaches (e.g., some form of casting and elevation) should be weighed against the 
need to apply study treatments and monitor outcome.  Similar considerations are important in 
choosing compression methods for venous stasis ulcers.   
 
c.  Maintenance of a moist wound environment 
 
Maintenance of a moist wound environment generally is accepted as a component of standard 
care for all chronic cutaneous ulcers.  Methods of maintaining a moist wound environment 
should be identified in the clinical protocol and optimized for the specific patient population, the 
wound type to be studied, and the type of product being tested.  If there is a sound rationale for 
the expected benefit of a test product that cannot be used with established standard care 
dressings, alterations in standard care might be safely implemented.  This can be done by 
including in the protocol adequate criteria for discontinuing subjects from study treatment or 
through the appropriate implementation of an independent data safety monitoring board to 
oversee trial safety.   
 
d.  Management of wound infection 
 
Effective control and management of infection is critical for treatment success of all wound-
treatment products, regardless of the claim.  For this reason, wound-treatment products that are 
  10 Contains Nonbinding Recommendations 
 
not intended for use as an anti-infective generally should be studied in subjects in whom the 
target ulcer is uninfected.  To this end, it is often appropriate to include in the trial design a run-
in period with standard therapies to control infection.   
 
In specific cases, such as the case of diabetic foot ulcers, wound-treatment products that are not 
anti-infective can be studied in wounds where infection is limited and responding to standard 
systemic antimicrobial therapy.  In trials involving infected ulcers it is especially important that 
the protocol clearly delineate adequate criteria for discontinuing subjects from study treatment 
because of wound deterioration during the treatment period (see section IV.H.3., Discontinuation 
of Treatment).  
 
If a subjects ulcer becomes infected during a study for a topical wound-treatment product, and 
the investigator prescribes topical antimicrobial treatment, the subject generally should be 
discontinued from study treatment.  (As for all discontinued subjects, safety assessment should 
continue throughout the trial and these subjects should be included in efficacy analysis).  
However, if sponsors anticipate that post-approval clinical use would likely entail concomitant 
topical products, the trial should be designed to address this variable.   
 
Systemic antimicrobial therapy for target wound infection may become necessary during the 
treatment period of the study.  Whether or not study treatment should be discontinued in this 
situation should be discussed prospectively and the plan included in the protocol.  For example, 
treatment discontinuation might be indicated in early trials, where little is known about product 
safety and where infection may signal test product-induced deterioration of the wound, but not in 
later trials in subjects for whom systemic antimicrobial therapy would be considered a 
component of standard care.   
 
e.  Nutritional support 
 
Nutrition is important to healing and immune competence, and should be tracked to allow 
assessment of this aspect of a subjects ability to heal.  Caloric intake and metabolic status 
should be captured in the CRFs if the product is known to have metabolic effects (e.g., anabolic 
steroids).  For products not known to have metabolic effects, these data may be useful if the 
inclusion criteria encompass subjects significantly above or below ideal body weight (e.g., 
cachectic subjects with pressure ulcers).  In studies of subjects with diabetic ulcers, it is 
important to record blood sugar levels because nutritional support with adequate blood sugar 
control is considered standard care for wound healing in these subjects.  
 
2.  Standard Care Considerations for Burns 
 
Standard care for serious burns includes careful attention to the following parameters: 
 
  Hemodynamic resuscitation 
  Management of co-morbidities 
  Timely burn debridement and excision 
  Wound closure 
  Management of wound infection 
  11 Contains Nonbinding Recommendations 
 
  Pain control 
  Nutritional support 
  Measures to inhibit excessive scar formation  
  Rehabilitation, including passive range of motion when burns overlie joints 
 
Because large burn centers tend to have well-established, distinct standard care regimens, 
randomization within multicenter burn trials may require stratification by center.  Since standard 
care procedures have profound effects on clinical outcome, every effort should be made to reach 
agreement among site investigators and to capture actual care delivered in the CRFs. 
 
G.  Efficacy Endpoints 
 
In general, clinical outcomes associated with the use of a wound-treatment product can be 
broadly grouped into two categories: improved wound healing and improved wound care.  Each 
outcome category includes a variety of potential endpoints for clinical trials.  Suggestions for 
possible outcome measures and clinical trial endpoints offered in this guidance are based on 
current knowledge of the natural history and management of burns and ulcers. 
 
1.  Improved Wound Healing 
 
a.  Incidence of complete wound closure 
 
Complete wound closure of a chronic, nonhealing wound is one of the most objective and 
clinically meaningful wound healing endpoints.  Complete wound closure is defined as skin re-
epithelialization without drainage or dressing requirements confirmed at two consecutive study 
visits 2 weeks apart.  Generally, trials to support an indication of complete wound closure 
measure incidence of complete wound closure in the treatment group and the control groups by a 
specified time (landmark analysis).  In the simplest case, a treatment effect would be established 
if a clinically and statistically significant greater proportion of subjects in the treatment group 
achieved complete wound closure compared to the control arm.  Timing of the endpoint 
measurements should be based on the natural history of the disease process, the anticipated time 
course for the treatment effect, and the expected response to standard care in the control arm.   
 
Trial subjects generally should remain in the study for follow-up evaluation at least 3 months 
following complete wound closure.  The purpose for this follow-up period is to help distinguish 
actual wound healing from transient wound coverage, determine if the product affects the 
strength of wound closure relative to standard care, and monitor for adverse effects on 
surrounding tissue (e.g., skin, bones, supporting structures). 
 
Measurement of partial wound healing in early phase clinical trials, if prospectively defined, may 
indicate relevant biological activity and help guide subsequent trial design.  Partial healing would 
not, however, suffice as a primary endpoint in phase 3 studies because the clinical benefit of 
incremental wound size changes has not been established.  However, partial healing that 
facilitates surgical wound closure can be a measurable trial endpoint of clinical benefit. 
 
  12 Contains Nonbinding Recommendations 
 
b.  Accelerated wound closure  
 
An indication of accelerated wound closure should reflect clinically meaningful reduction in the 
time to healing using a time-to-event analysis (the event being complete closure).  Assessments 
should be performed at intervals sufficiently frequent to detect a meaningful difference in time-
to-closure between treatment groups.  If claims are sought for both increased incidence of wound 
closure and accelerated healing, the study should be designed to detect both effects.   
 
Because partial thickness donor sites generally heal in 2 to 3 weeks with standard care regimens, 
when considering clinical endpoints for a product that accelerates closure of donor sites, the 
anticipated clinical benefit should be taken into account.  For example, a product that accelerated 
donor site healing by only 1 or 2 days might provide clinical benefit if it could be safely used in 
extensively burned patients requiring repeated re-harvesting of donor sites.  In studies where 
donor site wounds are chosen as the primary target for efficacy determinations, it is important to 
also assess the engraftment of tissue obtained by re-harvesting as a safety evaluation, because 
graft take should not be worsened by a product that accelerates healing of donor sites.  
 
c.  Facilitation of surgical wound closure  
 
If the claim sought is facilitation of surgical wound closure by partial healing, studies should be 
designed to measure the incidence of complete wound closure following the needed surgical 
procedure (such as flap closure of an extensive chronic pressure ulcer).  The durability and 
quality of the surgical wound closure should be assessed over time to ensure that the product 
does not have a deleterious effect. 
 
d.  Quality of healing (cosmesis and function) 
 
Studies evaluating the cosmetic aspects of quality of healing (cosmesis) can be designed to 
demonstrate a clinically significant effect on outcomes such as scarring, the contour and feel of 
the healed skin, or normalization of skin markings or pigmentation.  In choosing clinically 
relevant endpoints for an improved cosmesis claim, it is important to consider the type and 
location of wound (e.g., facial versus plantar surface of the foot) and whether a reliable 
assessment tool exists, or can be developed.  
 
Wound healing resulting in hypertrophic scar formation can be a source of long-term morbidity 
by inhibiting function (e.g., inhibition of range of motion across joints).  As such, wound-
treatment products that reduce hypertrophic scarring may also lead to improved function.  
Studies designed to evaluate the outcome of improved function through clinically relevant 
endpoints can be useful in supporting a labeling claim for function. 
 
2.  Improved Wound Care 
 
We recognize that products intended for wound management may provide important patient 
benefit without improving the incidence or timing of wound closure relative to standard care.  
However, it is important to demonstrate that such products do not significantly impede healing.  
  13 Contains Nonbinding Recommendations 
 
Thus, wound closure should be evaluated as a safety outcome for all products with a wound care 
claim.  
 
a.  Treatment of wound infection  
 
Infection at the wound site impairs healing.  Primary efficacy outcomes for topical antimicrobial 
wound-treatment products can thus be healing, prevention of, or cure of infection.  Such 
antimicrobial products generally should have an established and appropriate spectrum of 
antimicrobial activity.9   
 
b.  Debridement  
 
Debridement of necrotic tissue generally is considered part of standard care for most ulcers and 
burns.  Although there is debate about the optimal design of trials to assess the efficacy of 
debriding products, examples of clinically relevant endpoints include improved wound healing 
(increased incidence or acceleration of complete closure), reduced pain associated with the 
debridement process, or decreased blood loss during or immediately following debridement.  
When wound closure is not the chosen primary efficacy endpoint, the study should evaluate 
whether the debriding product impairs healing relative to standard of care. 
 
c.  Wound pain control 
 
Wound pain amelioration endpoints should be accompanied by assessment instruments that are 
prospectively defined and appropriate to measure the type of pain for which an indication will be 
sought.10  These studies should include, as a safety endpoint, an assessment of product effects on 
the healing process itself. 
 
3.  Temporary Dressings   
 
Temporary dressings, including interactive temporary dressings, are intended to provide 
supportive care until definitive closure can be accomplished.  Temporary dressings are expected 
to function as a barrier, much like human skin.  Trial endpoints other than healing should reflect 
one or more clinically relevant barrier functions, such as retardation of fluid loss or reduced 
infection rates.  If healing is not the primary efficacy endpoint, it should be evaluated as a safety 
endpoint. 
 
                                                 
9 In 1998, the Agency published a series of draft guidances on developing antimicrobial drug products.  Two of 
those guidances may be of interest: Developing Antimicrobial Drugs  General Considerations for Clinical Trials 
and Uncomplicated and Complicated Skin and Skin Structure Infections  Developing Antimicrobial Drugs for 
Treatment.  Once finalized, these guidances will reflect the Agencys views on developing antimicrobial drug 
products. 
 
10 For more information regarding endpoints, see the draft guidance for industry Patient-Reported Outcome 
Measures: Use in Medical Product Development to Support Labeling Claims.  Once finalized, this guidance will 
reflect the Agencys views on patient-reported outcome measures. 
  14 Contains Nonbinding Recommendations 
 
4.  Other Wound Care Claims 
 
Wounds can negatively affect many aspects of patients lives.  Clinically significant 
improvement in certain aspects of daily living (e.g., improvements in functional abilities) might 
support a labeling claim if appropriate trial endpoints measure a direct clinical benefit or if the 
endpoints are assessed with a clinically relevant validated instrument.11
 
H.  Safety Considerations  
 
1.  Immune Reactions 
 
For biological products and some drugs, immunogenicity generally is addressed by measuring 
antibody titers before and after the treatment.  Further immunological characterization with 
measures of the effect of antibody formation upon bioactivity, safety, and efficacy may be 
appropriate, since the development of an immune response can render the product inactive 
(neutralizing antibodies), and induce acute or chronic immune reactions (e.g., anaphylaxis, 
contact sensitization, autoimmune disease).  
 
2.  Trial Stopping Rules  
 
Because the patient populations in burn and chronic ulcer trials often have a high background 
incidence of serious adverse events, it is recommended that a safety data monitoring board be 
used for blinded trials when the known or suspected risk is significant, and the study population 
is critically ill (e.g., seriously burned patients).  Early in clinical development, sponsors may 
need to incorporate specific trial stopping rules based upon the occurrence of certain important 
adverse events, such as death or respiratory failure.  
 
3.  Discontinuation of Treatment 
 
Since the active ingredients or the vehicle of a topical wound-treatment product may have a 
deleterious effect on healing, subjects participating in early stage clinical trials generally should 
be discontinued from study treatment if signs or symptoms suggest wound deterioration.  Wound 
deterioration can manifest as erythema, pain, discharge, infection, tissue necrosis, requirement 
for repeat debridement or other surgical intervention (i.e., amputation), and increase in ulcer size.  
Undesirable alterations of soft tissues, ligaments, periosteum, or joint capsules underlying deep 
wounds also should be evaluated.  Once reasonable assurance has been achieved that the product 
does not harm the wound, it may be appropriate to continue study treatment in later trials, 
depending on the type of wound and patient population.  Subjects who are discontinued from 
study treatment should remain in the study for safety assessment and efficacy analysis.   
 
                                                 
11 For more information regarding endpoints, see the draft guidance for industry Patient-Reported Outcome 
Measures: Use in Medical Product Development to Support Labeling Claims.  Once finalized, this guidance will 
reflect the Agencys views on patient-reported outcome measures. 
  15 Contains Nonbinding Recommendations 
 
4.  Absorption Studies  
 
For topical drug, biological, and combination products, early clinical evaluations should include 
quantitation of absorption through the wound.  Systemic bioavailability of topically applied 
products is generally assessed using standard pharmacokinetic measurements with serial serum 
sampling.  Systemic uptake is influenced by wound factors such as size and vascularity, as well 
as product characteristics such as molecular weight, chemical composition, and the presence of 
excipients.  Systemic availability of a topical product may be profoundly influenced by wound 
bed preparation.  Thus, such studies should be performed when possible on a well-debrided 
wound as long as the debridement process is consistent with the methods of applying the 
investigational product and standard methods of wound care.  In the case of growth factors, 
relatively little (less than 1 percent) absorption typically occur from chronic ulcer sites, but these 
amounts might be clinically significant because some growth factors are active in vitro at 
nanogram concentrations.  For this reason, it is important to perform sensitive assays against 
serum background of the endogenous growth factor.  
 
For products that are absorbed from the wound bed, the systemic dose depends on several factors 
including the concentration of the active ingredient, the total body surface area treated, the 
volume applied, frequency of application, and duration of contact with the wound.  Safety and 
pharmacokinetic studies for topical wound-treatment products usually should be conducted in 
subjects with the indication sought, since absorption through intact skin of a healthy volunteer 
would not predict absorption in a wound.  
 
5.  Irritation and Contact Sensitization 
 
When preclinical studies or previous clinical experience suggest that a topical product might 
induce clinically significant dermatitis, irritation, or sensitization, we recommend that testing be 
done on intact skin before conducting clinical trials in chronic ulcers, wounds, or burns.  The 
testing is recommended because superimposed dermatitis can be deleterious to wounds.  The 
inclusion of routine testing of the final formulation depends on the product, and sponsors are 
encouraged to discuss dermal toxicity testing with the appropriate center before initiating the 
trials. 
 
I.  Statistical Considerations Specific for Wound-Treatment Product Trials 
 
This section addresses issues that present special considerations for wound-treatment product 
trials.12  
 
1.  Significance Tests 
 
Analysis should be prespecified in the protocol.  For incidence of closure endpoints, categorical 
techniques are recommended (e.g., Chi-square, tests of homogeneity, or logistic regression).  For 
time-to-closure endpoints, outcome survival analyses should be performed.   
 
                                                 
12 General guidance about data analyses also is available (e.g., ICH guidance for industry E9 Statistical Principles 
for Clinical Trials). 
  16 Contains Nonbinding Recommendations 
 
For wound-treatment product trials, the center or investigator is frequently included as a factor in 
the analysis, because of variations in standard of care.  Some analytical tests (e.g., Mantel-
Haenszel statistic and the Cox Proportional Hazards Model) allow for covariate adjustment.   
 
2.  Data Transformation and Covariate Analyses 
 
In the clinical trial design, prospective stratification in randomization should attempt to balance 
the trial arms for the one or two most important variables that are highly likely to affect the 
trials primary endpoint.  Covariate analyses can be employed to adjust for variables that affect 
the outcome.  If covariate analyses are used, the covariates and the analyses should be 
prespecified to avoid concerns about interpretability of significance tests.   
 
When analyzing covariates, experience suggests that it is generally not useful to transform 
continuous variables into dichotomous variables (e.g., baseline ulcer size greater than or equal to 
5 cm2 and duration of the ulcer more than 1 year).  The covariate should be used as a continuous 
variable.  Exploratory analyses can examine subgroups defined by various cut points, but when a 
particular cut point is deemed to be important in guiding the use of the product (e.g., ulcers 
greater than 10 cm2 do not respond), this cut point should be prospectively identified and studied 
in a clinical trial. 
 
 
V.  WOUND-TREATMENT PRODUCT QUALITY MICROBIOLOGY 
 
A wound represents a breach in the bodys natural barrier to microbial invasion; therefore, the 
final formulation of topical products used for the treatment of chronic ulcers, wounds, or burns 
should be sterile to avoid introducing exogenous microorganisms.  Guidance on validation of the 
manufacture of sterile products can be found in the guidance for industry Submission 
Documentation for Sterilization Process Validation in Applications for Human and Veterinary 
Drug Products.  Methods for performing sterility tests on drug products can be found in USP 
<71> Sterility Tests.   
 
To avoid contamination of a sterile product, it is preferable for wound-treatment products to be 
packaged in single-use containers.  However, if packaged in multi-use containers, wound-
treatment products should either include a preservative system or possess innate antimicrobial 
activity.  Antimicrobial preservatives should not be used as a substitute for good manufacturing 
practices.  The antimicrobial activity of the product, with (or without) a preservative system, 
should be demonstrated by performing a microbial challenge test such as USP <51> 
Antimicrobial Effectiveness Test.  The minimum acceptable limit for the content of preservatives 
(or other antimicrobial material, as in the case of an innately antimicrobial API) in a product 
should be demonstrated as microbiologically effective by performing a microbial challenge test 
of the formulation with an amount of preservative less than or equal to the minimum amount 
specified as acceptable.  For the purpose of application approval, stability data on pilot-scale 
batches should include results from microbial challenge studies performed on the product at 
appropriate intervals.  Typically, microbial challenge studies should be conducted initially, 
annually, and at expiration.  Chemical assays of preservative content also should be performed at 
all test points.  Upon demonstration of the antimicrobial effectiveness of the minimum specified 
  17 Contains Nonbinding Recommendations 
 
preservative concentration, chemical assays of the preservative may be sufficient to demonstrate 
the maintenance of adequate antimicrobial activity for annual batches placed into stability 
testing.  For biological products, testing should be done to ensure that the preservative does not 
compromise biological activity.   
 
Some products cannot withstand sterilization processes because they degrade when heated or 
irradiated, and they are not filterable.  If a wound-treatment product cannot be manufactured to 
be sterile, it should have a low bioburden.  Bioburden testing should be performed according to a 
validated test procedure such as in USP <61> Microbial Limit Tests and <62> Microbiological 
Examination of Nonsterile Products: Tests for Specified Microorganisms (when implemented) at 
appropriate, defined time points during stability studies.  Additionally, bioburden testing should 
include identification of recovered microorganisms to exclude potentially deleterious organisms.  
 
Refer to the following standards for validation of sterilization of medical devices:  
 
  ISO 11137:1995 Sterilization of health care products  Requirements for validation and 
routine control  Radiation sterilization 
  ISO 11135:1994 Medical devices  Validation and routine control of ethylene oxide 
sterilization 
  ISO 11134:1994 Sterilization of health care products  Requirements for validation and 
routine control  Industrial moist heat sterilization (available in English only) 
 
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