Epidermolysis Bullosa:  
Developing Drugs for 
Treatment of Cutaneous 
Manifestations  
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
 
June 2019 
Clinical/Medical 
   
:  
Epidermolysis Bullosa
Developing Drugs for 
Treatment of Cutaneous 
Manifestations  
Guidance for Industry 
 
Additional copies are available from: 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances 
 
 
 
 
 
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) 
 
June 2019 
Clinical/Medical 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  CONSIDERATIONS FOR CLINICAL TRIAL DESIGN .................................3 
A.  Trial Population ................................................................................................................. 3 
B.  Efficacy Endpoints ............................................................................................................ 4 
C.  Special Considerations ...................................................................................................... 5 
1. Junctional and Dystrophic Subtypes ................................................................................... 5 
2. EB Simplex .......................................................................................................................... 6 
 
 
  Contains Nonbinding Recommendations 
Epidermolysis Bullosa:  Developing Drugs for  
Treatment of Cutaneous Manifestations   
Guidance for Industry1 
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION 
 
The purpose of this guidance is to assist sponsors with the development of drugs2 for treatment 
or prevention of the serious cutaneous manifestations of the heterogeneous group of disorders 
collectively known as epidermolysis bullosa (EB).3  The paucity of effective treatment options 
for EB represents an important unmet medical need. 
 
This guidance focuses on drug development and trial design issues specific to the treatment of 
EB, including FDAs current thinking on trial endpoints.  There is not yet sufficient clinical trial 
experience to establish definitive endpoints.  
 
FDA strongly encourages sponsors to meet with the appropriate review division in early 
planning stages for information tailored to each drug development program.  
 
General issues, such as the efficacy evidence needed to support approval for serious and life-
threatening diseases or approaches to adaptive study design, are discussed in guidances for 
                                                 
1 This guidance has been prepared by the Division of Dermatology and Dental Drug Products and by the Rare 
Diseases Program in the Center for Drug Evaluation and Research in cooperation with the Center for Biologics 
Evaluation and Research at the Food and Drug Administration.  
 
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified. 
 
3 See the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics (May 2014).  
We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
1  Contains Nonbinding Recommendations 
industry,4 as are general issues of statistical analysis and control selection.5  In appropriate cases, 
a single adequate and well-controlled trial with confirmatory evidence may suffice for such 
conditions.  FDAs flexible approach to drug development for rare diseases in general, including 
the important topic of safety assessment, is also described in the draft guidance for industry Rare 
Diseases:  Common Issues in Drug Development (February 2019).6 
 
The following guidances for industry provide recommendations for products intended for 
cellular and gene therapies: 
 
  Guidance for industry Considerations for the Design of Early-Phase Clinical Trials of 
Cellular and Gene Therapy Products (June 2015) 
 
  Guidance for industry Gene Therapy Clinical Trials  Observing Subjects for Delayed 
Adverse Events (November 2006) 
 
  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) 
 
Some recommendations in the guidance for industry Chronic Cutaneous Ulcer and Burn Wounds 
 Developing Products for Treatment (June 2006) might be useful to developers of drugs for 
treatment of EB.  However, the wound healing guidance is intended for acute burn wounds and 
chronic venous stasis, diabetic foot, and pressure ulcers.  The distinct pathophysiology, natural 
history, and low prevalence of EB may justify and even warrant distinct approaches.  
 
In general, FDAs guidance documents 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 cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
II.  BACKGROUND 
 
EB encompasses a clinically and genetically heterogeneous group of rare inherited disorders 
characterized by mechanical fragility of epithelial tissues as a result of absent, reduced quantity 
of, or defective proteins integral to epithelial structure and function.  Epithelial integrity is 
                                                 
4 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological 
Products (May 1998) and the draft guidance for industry Adaptive Designs for Clinical Trials of Drugs and 
Biologics (September 2018) (when final, this guidance will represent the FDAs current thinking on this topic).  For 
the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents. 
 
5 See the ICH guidances for industry E9 Statistical Principles for Clinical Trials (September 1998) and E10 Choice 
of Control Group and Related Issues in Clinical Trials (May 2001), respectively. 
 
6 When final, this guidance will represent the FDAs current thinking on this topic.   
2  Contains Nonbinding Recommendations 
critical for protection and function of organs and tissues and prevention of water loss and 
infection.  In EB, defective epithelial integrity in the skin leads to chronic and relapsing wounds 
that predispose patients to repeated infections and may result in unwanted fibrosis and 
deformities as well as cutaneous carcinogenesis. Skin lesions are associated with itching and 
pain, the latter aggravated during dressing changes.  These complications and symptoms 
represent a major disease burden for patients. 
 
The classification of EB is evolving as new diagnostic techniques are developed.7  EB has been 
traditionally divided into major subtypes based on the level within which blisters develop:  
intraepidermal (EB simplex), within (junctional EB) or beneath (dystrophic EB) the skin 
basement membrane zone, and mixed pattern (Kindler syndrome).  More recent classification 
takes into account the mode of inheritance, phenotype, immunofluorescence antigen mapping 
findings, and gene defect.  There is considerable variation in disease severity and natural history 
within each EB subtype because of modifying genetic and other factors. 
 
 
III.  CONSIDERATIONS FOR CLINICAL TRIAL DESIGN 
 
A.  Trial Population 
 
  The trial population should have documentation of the clinical and laboratory evidence of 
the subtype(s) of EB that will form the basis of the proposed labeling claim (e.g., results 
of immunofluorescence antigen mapping or mutational analysis).  Genetic testing, if 
performed, should also be documented.  For some trials, mutational analysis may be 
important, and such data will need to be collected; however, it should not be a 
requirement for trial entry if this testing is not relevant to the desired claim.  In general, 
patients with adequate prior documented diagnosis do not need to have testing repeated. 
 
  As investigational products for cutaneous manifestations of EB can be directed at 

palliative treatment or be disease-modifying, the diagnostic method(s) used by a 
sponsor for the purposes of trial enrollment should be based on the characteristics of 
the specific development program, such as the following examples: 
 
  The investigational drugs mechanism of action, if known.  For example, a 
clinical trial for a product intended for palliation of EB wounds may not warrant 
extensive diagnostic work-up.  For a disease-modifying product (e.g., a gene 
therapy) a more extensive diagnostic workup is usually necessary.   
 
  The pathophysiology and natural history of the EB subtype(s) to be treated.  For a 
disease-modifying product designed to treat a specific subtype, it may be 
important to include mutational analysis. 
                                                 
7 Fine JD, Bruckner-Tuderman L, Eady RA, Bauer EA, Bauer JW, Has C, Heagerty A, Hintner H, Hovnanian A, 
Jonkman MF, Leigh I, Marinkovich MP, Martinez AE, McGrath JA, Mellerio JE, Moss C, Murrell DF, Shimizu H, 
Uitto J, Woodley D, Zambruno G, 2014, Inherited Epidermolysis Bullosa:  Updated Recommendations on Diagnosis 
and Classification, J Am Acad Dermatol, 70:11031126. 
 
3  Contains Nonbinding Recommendations 
 
  The clinical trial endpoints and efficacy assessment tools.  These should be 
relevant to the claims on the desired target population 
 
  Because EB subtypes differ in the extent and distribution of cutaneous wounds and the 
level of skin cleavage, results from an efficacy trial in EB simplex cannot be generalized 
to the more severe EB subtypes.  
 
  FDA encourages sponsors to discuss the desired trial population early with the review 
division.  The trial population should be representative of the phenotypic spectrum of 
interest, to the extent possible given the low prevalence of EB.  
 
  Because the junctional and dystrophic forms of EB generally present clinically at birth, 
sponsors should anticipate discussing with the review division the challenges of studying 
these EB subtypes in the newborn and in early infancy.  Sponsors also need to meet 
additional requirements for drug development in pediatric patients.8 
 
B.  Efficacy Endpoints 
 
  Sponsors should design clinical trials on EB to minimize bias using randomization to 
treatment and an appropriate control with blinded assessment of outcomes.  As EB is a 
rare disease, intrasubject randomization in early development to minimize sample size 
can be considered for topical drug product trials.  The trial endpoints can include effects 
on patients signs or symptoms such as itching, pain, blister prevention, wound healing, 
etc.  
 
  Before initiating clinical trials for EB, it is important for sponsors to discuss with the 

review division the choice of the primary efficacy endpoint(s), including whether the 
endpoint will be an effect on a continuous scale or on specified effect sizes (such as 
complete healing or a specified minimum degree of healing), as well as the time point 
for efficacy evaluation. 
 
  We encourage sponsors to propose endpoints for which there is (or will be before trial 

initiation) a validated and sufficiently sensitive assessment method to be used in EB 
clinical trials intended for regulatory review.  
 
  Patient-reported outcome (PRO) instruments9 and observer-reported outcome 

(ObsRO) instruments10 play an important role in establishing effectiveness of EB 
                                                 
8 See 21 CFR part 50, subpart D, Additional Safeguards for Children in Clinical Investigations. 
 
9 U.S. Food and Drug Administration and U.S. National Institutes of Health Biomarker Working Group, 2016, 
BEST (Biomarkers, EndpointS, and other Tools) Resource, Glossary Section Terms and Definitions under letter P, 
available at https://www.ncbi.nlm.nih.gov/books/NBK338448/#IX-P, accessed April 19, 2018. 
 
10 U.S. Food and Drug Administration and U.S. National Institutes of Health Biomarker Working Group, 2016, 
BEST (Biomarkers, EndpointS, and other Tools) Resource, Glossary Section Terms and Definitions under letter O, 
available at https://www.ncbi.nlm.nih.gov/books/NBK338448/#IX-O, accessed April 19, 2018. 
4  Contains Nonbinding Recommendations 
treatment because they provide evidence of how patients feel or function in daily life.  
Sponsors should incorporate patient and caregiver perspectives in efficacy endpoint 
development.  
 
  FDA is not aware of PRO or ObsRO instruments that have undergone evaluation 
for adequacy as measures to specifically assess cutaneous manifestations in the 
heterogeneous group of EB conditions in support of regulatory use.  Sponsors can 
submit existing or modified PRO, ObsRO, and/or clinician-reported outcome 
instruments for discussion and review. 
 
  The guidance for industry Patient-Reported Outcome Measures: Use in Medical 
Product Development to Support Labeling Claims (December 2009) provides 
information about developing such instruments.  
 
C.  Special Considerations 
 
Sponsors should consider development and validation of assessment tools and also consider 
processes that minimize visits to trial sites and maximize patient comfort, including assessment 
tools that may be more conveniently deployed  such as assessments performed at home visits.  
For example, sponsors can implement the following operational elements to achieve the above 
objectives:   
 
  Electronic informed consent 
 
  Telemedicine interactions with the assistance of mobile nurses as needed and their 
deployments for sample collection at patients homes 
 
  Photographic or video documentation of wounds during routine dressing changes in the 
home and at specified study visits for wound observation endpoint data, via standardized 
digital photographic images from photo capture and validated assessment of the images.  
The sponsor should discuss proposals for validation with FDA and reach agreement in 
advance of validation efforts 
 
  Validation and use of electronic PRO instruments 
 
  Data collection via electronic diaries 
 
In trials involving drug products intended for gene therapy, there should be assessments related 
to specific vector-based risks and long-term follow-up, especially for lentiviral vectors. 
 
1.  Junctional and Dystrophic Subtypes 
 
Trial recruitment and retention of patients with junctional and dystrophic subtypes of EB 
(characterized by extreme skin fragility) are challenging because trial procedures can exacerbate 
skin damage and increase the cost of intensive daily wound care to the patient.  In addition, 
5  Contains Nonbinding Recommendations 
because of the low prevalence of these subtypes, such patients may not live near specialty 
centers.  When designing clinical trials, FDA encourages sponsors to consider the following: 
 
  The importance of minimizing travel, which can lead to skin damage and pain 
 
  Identification of the essential aspects of skin care that must be standardized for trial 
interpretability versus those aspects that can remain patient or caregiver preference 
 
  Restriction of venipuncture and other procedures to those essential to efficacy evaluation, 
safety monitoring, and pharmacokinetic studies.  For enrolled patients with extracutanous 
manifestations, trial procedures and sample collection should coincide with patient care 
procedures performed under sedation 
 
2.  EB Simplex 
 
For sponsors developing drugs to treat EB simplex, seasonal timing and geographic location of 
trial enrollment should address the disease-modifying influence of ambient temperature and 
physical activity. 
6