Duchenne Muscular 
Dystrophy and Related 
Dystrophinopathies:  
Developing Drugs for 
Treatment  
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) 
 
February 2018 
Clinical/Medical 
 
   
Duchenne Muscular 
Dystrophy and Related 
Dystrophinopathies:  
Developing Drugs for 
Treatment   
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
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https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
and/or 
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https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
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) 
 
February 2018 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DEVELOPMENT PROGRAM ....................................................................................... 2 
A.  General Considerations .................................................................................................................2 
1. Early Phase Clinical Development Considerations .........................................................................2 
2. Drug Development Population .........................................................................................................3 
3. Efficacy Considerations ...................................................................................................................4 
4. Safety Considerations .......................................................................................................................4 
B.  Specific Efficacy Trial Considerations .........................................................................................5 
1. Study Design .....................................................................................................................................5 
2. Study Population ..............................................................................................................................5 
3. Efficacy Endpoints ............................................................................................................................6 
4. Study Procedures and Timing of Assessments ..................................................................................9 
5. Endpoint Adjudication ......................................................................................................................9 
6. Statistical Considerations ...............................................................................................................10 
7. Accelerated Approval Considerations ............................................................................................10 
8. Benefit-Risk Considerations ...........................................................................................................11 
C.  Other Considerations ...................................................................................................................12 
1. Relevant Nonclinical Safety Considerations ..................................................................................12 
2. Pharmacokinetic/Pharmacodynamic Considerations ....................................................................12 
3. Labeling Considerations ................................................................................................................13 
 
 
  Contains Nonbinding Recommendations 
Duchenne Muscular Dystrophy and Related Dystrophinopathies:  
Developing Drugs for Treatment  
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 
 
This guidance addresses FDAs current thinking regarding clinical development programs and 
trial designs for drugs to support an indication for the treatment of one or more 
dystrophinopathies:  Duchenne muscular dystrophy (DMD) and related dystrophinopathies 
including Becker muscular dystrophy (BMD), DMD-associated dilated cardiomyopathy (DCM), 
and symptomatic carrier states in females.2, 3  The most prominent pathology in 
dystrophinopathies is degeneration of skeletal and cardiac muscle leading to progressive loss of 
muscle function, respiratory and cardiac failure, and premature death.  This guidance does not 
address the development of drugs to treat secondary complications of muscle degeneration in 
dystrophinopathies (e.g., drugs specifically for heart failure or pulmonary infections).  
 
This guidance does not contain discussion of the general issues of statistical analysis or clinical 
trial design, as these topics are addressed in the ICH guidances for industry E9 Statistical 
Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical 
Trials, respectively.4  
                                                 
1 This guidance has been prepared by the Division of Neurology Products in the Center for Drug Evaluation and 
Research in cooperation with the Center for Biologics Evaluation and Research (CBER), 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 In addition to consulting guidances, sponsors are encouraged to contact the division to discuss specific issues that 
arise during the development of drugs for the treatment of dystrophinopathies.  
 
4 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
Drugs or Biologics guidance web pages at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
1  Contains Nonbinding Recommendations 
 
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 
 
Dystrophinopathies result from genetic mutations in the dystrophin gene that decrease the 
amount of dystrophin protein and/or cause dysfunction of the protein.  Protein dysfunction leads 
to muscle degeneration and, in many patients, downstream pathologies including inflammation 
and fibrosis that interfere with muscle regeneration and cause loss of movement, orthopedic 
complications, and, ultimately, respiratory and cardiac failure.  The most common and generally 
most severe dystrophinopathy is DMD, with a birth prevalence of about 1 in 3,500 to 6,000 
males.  DMD causes delay and/or failure to reach developmental milestones, functional losses in 
the first decade of life, and greatly decreased life expectancy.  BMD generally has later onset of 
symptoms and slower progression.  BMD is characterized by wide interpatient variability in 
severity, with some patients having a clinical course similar to that observed for DMD, while 
other patients remain nearly, or in some cases completely, asymptomatic.  The birth prevalence 
of BMD is about 1 in 20,000 males.  DCM is less common and caused by dystrophin mutations 
that primarily affect cardiac muscle.  Finally, some female carriers of dystrophin mutations 
experience muscle degeneration similar to that in males. 
 
 
III.  DEVELOPMENT PROGRAM 
 
A.  General Considerations 
 
1.  Early Phase Clinical Development Considerations 
 
For a variety of reasons, communication between drug developers and those affected by 
dystrophinopathies is important during the development of drugs for these conditions, to discuss 
expectations with respect to both efficacy and safety. 
 
  FDA recognizes that those affected by life-threatening and severely debilitating illnesses 
with unmet medical need are generally willing to accept greater risks and greater 
uncertainties about risks.5  It is important that drug developers understand how affected 
individuals view treatment goals and risk tolerance as well the relationship between treatment 
goals and risk tolerance to a patients specific circumstances.  For example, tolerance for risk 
may differ between patients with the more severe and less severe dystrophinopathy 
phenotypes.  As development proceeds and the potential benefits and risks of a drug become 
                                                 
5 21 CFR 312.80, subpart E. 
2  Contains Nonbinding Recommendations 
more clearly understood, drug developers should elicit further input from patients and 
caregivers.  
 
  Many patients with dystrophinopathies are children.  Special considerations apply to the 
conduct of studies in children and the types and contexts of risks that are considered to be 
ethically acceptable.6  Within the bounds of these ethical considerations, in studies where 
the risk to children is more than minimal,  drug development studies may be allowed to 
proceed under FDAs regulatory framework if the risk is justified by the anticipated 
benefit to the child and the relation of the anticipated benefit to the risk is at least as 
favorable as that presented by available alternative approaches .7  However, patients and 
caregivers can make appropriate decisions about participation in clinical studies only if 
provided with clear information about the potential risks and benefits.  In addition to 
informed consent, and assent by children, if applicable, based on information available at 
the beginning of the study, it is critical that emerging safety information be 
communicated rapidly to study patients and their caregivers on an ongoing basis to allow 
them to reassess continued participation.  
 
  Treatment goals similarly may differ, depending on patient-specific circumstances such 
as age and disease stage.  Patients most severely affected by the disease, along with their 
caregivers, can provide insight into the outcomes that are most appropriate to designate as 
primary endpoints, how these outcomes might best be assessed, and the meaningfulness 
of treatment effects when considered in the context of the overall disease.  
 
2.  Drug Development Population 
 
There is a need to understand the safety and efficacy of investigational drugs for 
dystrophinopathies across disease stages and phenotypes.  Although drug developers may have 
good reasons to use prognostic enrichment to increase the likelihood of demonstrating a drug 
effect (e.g., to enroll patients who are more likely to experience rapid progression) or to use 
predictive enrichment to direct therapy to patients with a particular disease characteristic (e.g., a 
specific genotype or phenotype), drug developers should not unnecessarily exclude patients from 
enrollment based on characteristics such as age or disease stage unless scientifically justified.  
Broader inclusion criteria allow more rapid trial enrollment, potentially accelerating drug 
development.  Demonstrating safety and efficacy of an investigational drug generally involves 
several stages of development and a number of clinical trials, increasing the feasibility of 
including patients across different disease stages and phenotypes.   
 
There is a strong rationale for treatment of patients at an early age because drugs that preserve 
muscle, in particular, may have the greatest effect on prognosis before muscle health has 
deteriorated.  There is also a need to assess safety and efficacy of drugs at later phases of disease, 
however, including stages when respiratory and cardiac pathology is more pronounced.   
 
                                                 
6 21 CFR part 50, subpart D.  
 
7 21 CFR 312.42. 
3  Contains Nonbinding Recommendations 
3.  Efficacy Considerations 
 
The statutory standards for effectiveness apply to drugs for dystrophinopathies just as the 
standards apply for all other drugs.  FDA has long stressed, however, that it is appropriate to 
exercise flexibility in applying the statutory standards to drugs for serious diseases with unmet 
medical needs, while preserving appropriate guarantees for safety and effectiveness.8  
 
4.  Safety Considerations 
 
Trials in dystrophinopathies generally should be conducted under the oversight of a data 
monitoring committee (DMC).  The DMC should look for emerging safety signals at frequent 
intervals and, if necessary, advise the sponsor regarding appropriate measures to ensure that 
patients are not placed at unreasonable risk of harm.9  
 
To support marketing approval, drug risks must be characterized with an adequate number of 
patients and an adequate duration of exposure.10  FDA generally will consider the serious and 
life-threatening nature of DMD and other severe dystrophinopathies when determining the 
minimum number and duration of patient exposures needed.11  Drugs shown to provide an 
important benefit will generally need less safety data to provide adequate assurance that benefits 
outweigh risks.  During development, sponsors should collect safety data, including data from 
open-label studies or expanded access programs, from patients across the spectrum of disease 
stages and severities, and, whenever possible, data from patients who may not have been 
included in efficacy studies but in whom, based on other data, the use of the drug following 
approval is likely.  Safety data from a reasonable number of patients exposed to the drug for at 
least 1 year generally is appropriate to support approval of drugs intended for chronic use in 
treating DMD and other severe dystrophinopathies.  
 
Adverse events of special interest for drugs for the treatment of dystrophinopathies include 
those related to immune responses to dystrophin or other muscle components.  Exacerbation of 
cardiac disease may be a concern for drugs that increase physiological stress on the heart by 
increasing the amount or activity of skeletal muscle or for drugs that could directly affect 
cardiac dystrophin.  
 
                                                 
8 21 CFR 312.80, subpart E, Drugs Intended to Treat Life-Threatening and Severely-Debilitating Illnesses. 
 
9 See the guidance for clinical trial sponsors Establishment and Operation of Clinical Trial Data Monitoring 
Committees.  
 
10 21 CFR 314.125(b)(2). 
 
11 21 CFR 314.105(c); FDA is required to exercise its scientific judgment to determine the kind and quantity of data 
and information a sponsor is required to provide for a particular drug to meet the statutory standards. 
4  Contains Nonbinding Recommendations 
B.  Specific Efficacy Trial Considerations 
 
1.  Study Design 
 
FDA strongly recommends randomized placebo-controlled trials, which generally are the most 
efficient way to demonstrate efficacy of drugs to treat dystrophinopathies.  In some 
circumstances, however, FDA may consider trials using external controls (historically controlled 
trials) to be adequate and well controlled studies that may contribute to evidence of efficacy to 
support approval.  However, FDA recognizes that historically controlled trials lack important 
design features that reduce bias, such as randomization and masking of treatment assignment and 
generally are persuasive only when drug effects are large on objective endpoints that are less 
susceptible to bias.12  (Expectation bias can increase motivation in patients who know they are 
receiving active treatment, thereby improving patient performance on functional tests.)  To 
support reliance on externally controlled studies, a sponsor should present detailed evidence that 
the study design and conduct are adequately controlled for bias.  For example, it would be 
critical to establish that the control group was prospectively well matched to the treatment group 
across important baseline and prognostic variables, including age, baseline value of the primary 
efficacy measure and other measures of disease stage, type and intensity of supportive care, dose 
and duration of concomitant pharmacotherapies, and genotype, among others.  Potential sources 
of bias, such as differences in encouragement during tests of physical performance or function, 
should be eliminated or minimized.  The disease course in an external patient cohort can be 
sensitive to the date of inception and the age of patients at inception.  Thus, selection of these 
parameters with data in hand can introduce bias.  Again, because of the inherent limitations of 
externally controlled trials, only large treatment effects are likely to be convincing.  
 
2.  Study Population 
 
Although there is a need to characterize the safety and efficacy of investigational drugs for 
dystrophinopathies across multiple disease stages and phenotypes, a sponsor can target drug 
development to an identified disease subgroup when scientifically justified (e.g., drugs that are 
directed at specific dystrophin mutations).  Similarly, sponsors can base enrollment on early 
biomarker data that suggest clinical benefit is likely to occur in only a subset of patients that can 
be identified using that biomarker.   
 
For drugs that may slow clinical decline but are not expected to improve or reverse preexisting 
muscle dysfunction, it may be useful to consider prognostic enrichment (i.e., the use of inclusion 
criteria to select patients with characteristics that predict more rapid clinical decline during the 
planned study).  Such criteria might include a history of rapid deterioration before study entry or 
more severe functional deficit at enrollment.  For more information on prognostic enrichment, 
see the draft guidance for industry Enrichment Strategies for Clinical Trials to Support Approval 
of Human Drugs and Biological Products.13 
 
                                                 
12 See ICH E10. 
 
13 When final, this guidance will represent the FDAs current thinking on this topic.  
5  Contains Nonbinding Recommendations 
For drugs targeted to specific mutations, sponsors need to identify accurately the dystrophin 
mutation(s) of each patient for enrollment.  Even for drugs intended to have mutation-
independent efficacy, FDA strongly recommends testing because knowledge of genotype-
phenotype correlations may reveal differences in safety and efficacy across subgroups.  For 
similar reasons, FDA also strongly recommends genotyping additional loci that modify 
phenotype.   
 
For drugs in which efficacy or safety may be related to the patients specific dystrophin mutation 
or to another type of finding related to a biomarker for which a suitable diagnostic device is not 
available, a sponsor should develop contemporaneously a companion diagnostic device.  The 
sponsor should establish the clinical performance characteristics of the diagnostic device using 
data from the clinical development program of the drug.  Given the serious and life-threatening 
nature of dystrophinopathies and the lack of satisfactory alternative treatments that currently 
exist, however, FDA may approve a drug even if a companion diagnostic device is not yet 
approved or cleared, if the benefits from the drug are so pronounced as to outweigh the risks 
from the lack of an approved or cleared in vitro companion diagnostic device.14  During the drug 
review, FDA will determine the need for clearance or approval of the device.  We encourage 
sponsors to engage early in development with the Division of Neurology Products or the Center 
for Devices and Radiological Health at FDA to discuss the potential need for the codevelopment 
of a companion diagnostic device 
 
3.  Efficacy Endpoints 
 
FDA has no defined set of required or recommended clinical outcome measures for studies in 
dystrophinopathies.  Although existing outcome measures developed for clinical trials and/or 
clinical care in dystrophinopathies or related conditions may be appropriate, FDA will also 
consider proposals for the use of novel outcome measures that are capable of measuring 
clinically meaningful effects in patients.  FDA encourages sponsors to propose and, if necessary, 
develop endpoints that can validly and reliably assess patients with a wide spectrum of 
symptoms and disease stages.  Sponsors should engage FDA early during the selection and/or 
development of efficacy endpoints.  The sponsor should include an assessment of multiple 
efficacy endpoints, when feasible, to characterize the breadth of effects on dystrophin-related 
pathologies, including skeletal, respiratory, and cardiac muscle function, even if the primary 
endpoint is only one of these measures. 
 
Efficacy endpoints that can measure change of function over a wide range of types and severity 
of deficits may offer a number of advantages in the development of drugs for dystrophinopathies.  
Such endpoints may increase the number of patients eligible for enrollment and may decrease 
possible loss of information from floor and ceiling effects that occur, respectively, when patients 
become unable to contribute data because they can no longer complete a function, or remain 
capable of performing a function throughout the study.  For similar reasons, FDA encourages 
sponsors to use endpoints that can assess function across different stages of the disease (e.g., by 
                                                 
14 See the guidance for industry and Food and Drug Administration staff In Vitro Companion Diagnostic Devices 
available at 
https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm081752.htm.  
6  Contains Nonbinding Recommendations 
combining measures of ambulation and upper body function).  Endpoints should have the ability 
to detect improvement from baseline, as well as decline, to capture the spectrum of possible 
beneficial drug effects.  
 
Patient-reported outcomes (PROs),15 including those measuring activities of daily living, can be 
designed to assess the abilities and experiences of patients across a spectrum of disease stages 
and severities.  PROs can be useful to assess the clinical meaningfulness of an objective finding 
of relatively small magnitude and to contribute to assessments of benefit and risk.  PRO 
instruments for dystrophinopathies generally should include a limited number of items that 
assess the most important aspects of the outcome of interest (e.g., specific aspects that contribute 
to health-related quality of life, such as physical functioning).  PRO instruments that are overly 
lengthy may increase responder burden and fatigue, increasing the potential for missing data.  
PRO instruments that are overly broad can be difficult to interpret and may be insensitive to 
meaningful change in the outcomes of major interest.  In cases where a patient is unable to report 
for himself or herself (e.g., a young child), the sponsor should base observer-reported outcomes 
on what a caregiver or other observer directly sees during a patients daily activities. 
 
Sponsors can measure efficacy endpoints based on function in a variety of ways, including 
performance-based outcome assessments that demonstrate the patients ability to perform a 
specific activity or set of activities (e.g., ability to perform the activity(ies) (yes or no); time 
required to perform the activity(ies)) or as time to event for decline or loss of an ability.  For 
young children in whom abilities are still developing, it may be appropriate to assess time to 
event in the positive sense (i.e., the time to reach a certain developmental milestone). 
 
Additional considerations for endpoints include the following: 
 
  In neonates, infants, and young children up to 4 years of age, developmental scales have 
been used in DMD (e.g., the Griffiths Scale of Mental Development or Bayley Scales of 
Infant and Toddler Development, Third Edition).  However, sponsors should discuss with 
the FDA, and reach agreement on, the appropriateness of the use of such scales in clinical 
trials. 
 
  In ambulatory children ages 3 years and older, the North Star Ambulatory Assessment or 
an age-appropriate modified North Star Ambulatory Assessment can provide a useful 
measure of gross motor function, as can timed function tests such as time to climb four 
stairs or time to walk or run 10 meters, among others. 
 
  Myometry may be an appropriate endpoint for treatments that increase or preserve 
muscle strength, and it can be used to provide reliable measurements in children ages 5 
years and older.  The clinical meaningfulness of differences in muscle strength should be 
supported by the magnitude of the effect observed or by the demonstration of a drug 
effect on an appropriate functional measure.  In some instances, a demonstrated effect on 
                                                 
15 A PRO is a measurement based on a report that comes directly from the patient (i.e., study subject) about the 
status of the patients health condition without amendment or interpretation of the patients response by a clinician 
or anyone else.  
7  Contains Nonbinding Recommendations 
muscle strength could be considered an intermediate clinical endpoint and be used to 
support accelerated approval.16 
 
  The 6-minute walk test (6MWT) or shorter versions such as the 2-minute walk test, can 
measure both strength and endurance, and can be appropriate for patients as young as 5 or 
6 years of age.  There are challenges associated with the use of these tests.  First, 
performance tends to improve with time in very young patients whereas performance 
tends to worsen with time in older patients.  Second, there can be a floor effect of losing 
ambulation in older patients with more advanced disease.  Analyses of change in 6MWT 
can be strongly influenced by the inclusion or exclusion of patients who lose ambulation 
during the trial; such patients contribute zero values.  Third, considering the above, the 
data may not be normally distributed, which can have important analytical ramifications. 
 
  For older nonambulatory patients, a number of outcome measures are available that 
measure primarily upper extremity function.  
 
Many functional endpoints in clinical trials for dystrophinopathies include tasks performed by a 
patient in a clinical setting according to instructions administered by a health care professional.  
Such endpoints can be affected by the effort of the patient and/or coaching or encouragement by 
a family member, caregiver, or medical staff so that blinding to treatment is critical.  Sponsors 
should consider other ways to minimize such influences.  For example, sponsors should 
standardize the encouragement given to patients during testing, and whenever practicable, study 
personnel who are not aware of clinical course or potentially unmasking adverse events should 
administer tests of functional endpoints.  
 
Efficacy in dystrophinopathies can also be demonstrated by an effect on respiratory and/or 
cardiac endpoints, with the following considerations:  
 
  Specific clinical respiratory outcomes can include nocturnal desaturation, aspiration 
pneumonia, and progression to mechanically assisted ventilation.  Additional measures of 
respiratory function, such as vital capacity, maximal inspiratory pressure, and maximal 
expiratory pressure can also be used.  As with myometry, sponsors should support the 
clinical meaningfulness of differences in these additional measures by examining the 
magnitude of the effect observed (both mean effect and distribution of responses) or by 
the demonstration of a drug effect on an adequate functional measure.  In some instances, 
a demonstrated effect on these measures could be considered an intermediate clinical 
endpoint and used to support accelerated approval.  
 
  Evidence of effectiveness in chronic heart failure has traditionally relied on randomized, 
double-blind clinical trials in adult patients with documented heart failure and/or left 
ventricular dysfunction caused by common etiologies such as ischemic heart disease, 
hypertension, or myocarditis.  Most of these trials have been designed to detect outcomes 
such as improved survival or a composite of improved survival and decrease in heart 
                                                 
16 See the guidance for industry Expedited Programs for Serious ConditionsDrugs and Biologics.  
8  Contains Nonbinding Recommendations 
failure hospitalizations.  These trials have not used improved exercise capacity alone as 
an endpoint, at least in part, because heart failure treatments that have improved exercise 
capacity have had adverse effects on survival.  A treatment for DMD directed at the 
underlying disease pathology might pose fewer such concerns so that FDA could 
consider improved exercise capacity alone to be an appropriate endpoint.  One obvious 
disadvantage of an approach demonstrating improvement in exercise capacity is that the 
effects of skeletal muscle function and cardiac muscle function might not be easily 
distinguished. 
 
  Few natural history studies exist for patients with DMD cardiomyopathy, which increases 
the difficulty of developing measures that might predict disease progression or serve as 
endpoints for accelerated approval.  FDA recommends that, whenever feasible, sponsors 
collect the following cardiac data during clinical trials:  periodic evaluation of signs and 
symptoms of cardiac involvement or heart failure that are appropriate for the age and 
disease stage of the trial population, inventory of cardiac medications, serial 
electrocardiograms, and serial noninvasive imaging studies (e.g., echocardiography or 
cardiac magnetic resonance imaging). 
 
Dystrophin is expressed in the brain, and dystrophinopathies can be associated with cognitive 
and behavioral effects.  Although many drugs that affect behavior would not be considered 
dystrophinopathy-specific (e.g., drugs for attention deficit hyperactivity disorder), FDA could 
approve a drug for dystrophinopathies if a specific beneficial effect on the nervous system were 
demonstrated (i.e., the benefit would not be expected to occur in patients without dystrophin 
mutations).  
 
4.  Study Procedures and Timing of Assessments 
 
Drugs that will be chronically administered to patients with dystrophinopathies should be shown 
to be effective for a period of at least 3 months.  For drugs expected to slow functional decline, 
study length necessarily is affected by the rate of progression in addition to predicted drug 
efficacy.  Although studies of 1 years duration have been conducted in DMD, sponsors should 
base the duration of studies on scientifically justifiable sample size calculations that include, 
when appropriate, the predicted rate of functional decline in the placebo group, the anticipated 
effect size, the variability around these estimates, and the desired statistical power.  Efficacy 
studies of 18 to 24 months duration may substantially increase statistical power, while only 
modestly increasing overall development time. 
 
5.  Endpoint Adjudication 
 
Blinded adjudication of cardiac endpoints has commonly been used in studies of cardiovascular 
drugs, and sponsors should consider this if cardiac endpoints (e.g., heart failure, cardiac 
hospitalizations) are used.  Sponsors should also consider adjudication for complex respiratory 
endpoints (e.g., aspiration pneumonia) because equivocal cases may occur.  Functional 
endpoints (e.g., the ability to rise from the floor, to walk) potentially may benefit from 
adjudication to address potential confounding factors such as reversible injury. 
 
9  Contains Nonbinding Recommendations 
6.  Statistical Considerations 
 
In general, statistical approaches for dystrophinopathies should be similar to those used in other 
disease areas, as described in other guidances.  Sponsors can use designs that increase the 
efficiency of studies (e.g., adaptive designs17).  
 
For efficacy assessment based on a continuous measurement of functional capacity, sponsors 
generally should perform statistical analyses on the change from baseline for each treatment 
group, with the treatment effect assessed by comparing the mean changes between the treatment 
and control groups at one or more specific times.  The mean changes would normally be adjusted 
for the baseline measurement to improve statistical power for detecting a treatment effect. 
 
Overall, a study should be adequately powered to be able to detect a treatment effect in the study 
population taking into account the estimated effect size.  Because of the limited number of 
patients with DMD, however, it may not be realistic or feasible to adequately power the study to 
attain statistically significant results for each distinct subpopulation of interest in the study.  If 
the sponsor has obtained statistically significant results demonstrating efficacy in the overall 
target population, favorable trends in the efficacy results may support the inclusion of a 
description of subpopulations within the clinical trials section of labeling. 
 
Sponsors can decrease variability by obtaining a baseline assessment on more than one occasion, 
if practicable (e.g., performing a 6MWT on two occasions, 1 week apart).  For studies that 
require a specific degree of physical disability for enrollment (e.g., a 6MWT distance of less than 
350 meters), the screening assessment used to qualify patients for study entry should not be used 
as the baseline assessment.  A sponsor should obtain a separate baseline assessment after the 
screening assessment to limit regression to the mean.  For dystrophinopathies, sponsors can also 
consider a variation of this approach that assesses the change from baseline in the slopes (or rates 
of change).  Whereas the typical change from baseline assessment takes only two measurements 
into consideration (pretreatment and posttreatment at a particular time point), assessment of 
slope change takes multiple measurements into consideration for each patient, thereby possibly 
improving statistical power to show a treatment difference. 
 
The likelihood that randomization will be fully successful in producing comparable study arms 
can be increased through stratified randomization based on one or more prognostic factors.  For 
young children, stratification might be based on markers of lower-limb strength or ambulatory 
abilities, whereas for older children, pulmonary and cardiac status might be appropriate 
stratification factors.  With small to moderate sample sizes, however, sponsors should limit such 
covariates to a few that are carefully chosen. 
 
7.  Accelerated Approval Considerations 
 
In dystrophinopathies, biomarkers that reliably reflect the health and amount of skeletal muscle 
at a biochemical, cellular, or tissue level may be useful across the drug development process, 
                                                 
17 See the draft guidance for industry Adaptive Design Clinical Trials for Drugs and Biologics.  When final, this 
guidance will represent the FDAs current thinking on this topic.  
10  Contains Nonbinding Recommendations 
including use as prognostic, predictive, or pharmacodynamic markers, or, in some instances if 
supported by sufficient scientific evidence and acceptable analytical methods, as surrogate 
endpoints to support accelerated approval.  A single biomarker measure can, in different 
circumstances, serve different functions; for example, baseline dystrophin expression can be a 
marker of a patients prognosis whereas an increase in dystrophin could reflect biological 
activity of a drug and guide key aspects of drug development such as dose selection and route of 
administration.  Even if it cannot be concluded that a given biomarker can serve as a surrogate 
endpoint, positive findings based on a biomarker may help support the mechanism of action of a 
drug, help identify the appropriate patient population to study or treat, or support the validity of 
findings on other endpoints.  To support continued progress in overall drug development for 
dystrophinopathies, trials with clinically meaningful endpoints should include a selection of 
relevant biomarkers to help establish the correlation between such biomarkers and clinical 
endpoints.  
 
The potential for a biomarker to predict clinical benefit in dystrophinopathies could relate to the 
magnitude of change of the biomarker and tissue in which the biomarker is measured.  The 
meaning of a change in a biomarker might also depend on the age or disease stage of a patient or 
on other patient factors such as inflammation or autoimmunity to dystrophin or other muscle 
components.  When biomarkers are assessed, analytical validity should be demonstrated to the 
extent possible, and there should be adequate assessment of the performance characteristics of 
the biomarker assay, including quality-control measures and documentation of results.  
 
Deficiency of functional dystrophin appears to be the proximate cause of the symptomatic and 
functional consequences of dystrophinopathies, justifying particular interest in dystrophin as a 
biomarker and as a potential surrogate endpoint for accelerated approval.  
 
FDA also encourages sponsors to consider the use of other biomarkers, such as those measured 
with magnetic resonance imaging or magnetic resonance spectroscopy.  Advantages of imaging 
include its noninvasiveness, its ability to assess large samples of muscle, the fact that it can be 
performed repeatedly at multiple time points, and its ability to assess multiple regions of the 
body, including cardiac muscle.  
 
Sponsors considering a development program intended to support accelerated approval should 
discuss their development programs with the Division of Neurology Products early in drug 
development. 
 
8.  Benefit-Risk Considerations 
 
When making regulatory decisions regarding drugs for dystrophinopathies, FDA will consider 
patient and caregiver tolerance for risk and the serious and life-threatening nature of these 
conditions.  For example, patients may be willing to tolerate substantial risk of harm if a drug 
might delay loss of important abilities such as ambulation.  However, tolerance for risk may 
vary among individuals and be affected by disease stage and severity; FDA would consider this 
heterogeneity in regulatory decisions. 
 
11  Contains Nonbinding Recommendations 
C.  Other Considerations 
 
1.  Relevant Nonclinical Safety Considerations 
 
Nonclinical studies provide important information upon which it can be determined whether 
clinical trials are reasonably safe to conduct, and to inform clinical dose selection and 
monitoring.  For serious and life-threatening diseases for which treatments are not available or 
are inadequate, as a general matter, it may be appropriate to permit clinical trials to commence 
based on less than usual nonclinical testing if scientifically justified.  In certain cases, the 
duration of dosing in human studies may exceed that of the nonclinical studies if justified based 
on the available nonclinical and clinical data.  Sponsors are encouraged to consult with the 
Division of Neurology Products early in clinical development. 
 
Studies in juvenile animals, to assess the potential for toxicity to immature systems and 
developmental processes, should be conducted to support clinical studies in the pediatric 
population.  The design of studies in juvenile animals18 and timing of submission during clinical 
development should be discussed with the Division prior to study initiation.  Carcinogenicity 
studies generally can be conducted after approval for drugs intended to treat most 
dystrophinopathies. 
 
2.  Pharmacokinetic/Pharmacodynamic Considerations 
 
Given the serious and life-threatening nature of diseases such as DMD and other severe 
dystrophinopathies, the typical array of clinical pharmacology testing is unlikely to be needed to 
support a new drugs approval.  For example, FDA can defer until after approval, or waive, 
studies of effects of renal or hepatic impairment if the patient population and metabolic pathways 
of the drug, considered together, suggest a low likelihood of clinically meaningful effects on 
pharmacokinetics or pharmacodynamics.  FDA encourages sponsors to consult with the Division 
of Neurology Products early in clinical development. 
 
Sponsors should define and evaluate as needed the pharmacokinetic and/or pharmacodynamic 
interactions between an investigational new drug and other drugs commonly used in 
dystrophinopathies during drug development as part of an adequate assessment of the drugs 
safety and effectiveness.  Concomitant use of supplements, herbals, and dietary modifications is 
common in dystrophinopathies, and sponsors should consider the potential effects of these on the 
pharmacokinetics and pharmacodynamics of investigational drugs.  
 
Sponsors should explore the relationship between exposure (drug concentration in plasma or 
other biological fluid) and efficacy and safety endpoints.  Exposure-response relationships using 
biomarkers from early dose-finding studies can help identify dose/dosing regimen(s) for 
confirmatory studies and the need for dose adjustment for various extrinsic/intrinsic factors such 
as drug-drug interactions, age, and renal function, among others.  Importantly, exposure-response 
assessment can also contribute to evidence of effectiveness from confirmatory studies.  The 
                                                 
18 Such studies may not be needed for gene or cell therapy products regulated by CBER.  Sponsors should consult 
with CBER early in clinical development to discuss the need for juvenile animal toxicology studies.  
12  Contains Nonbinding Recommendations 
response variables used in the analyses should include prespecified primary and secondary 
endpoints, as well as results involving biomarkers collected in the studies for efficacy and safety.  
 
3.  Labeling Considerations 
 
FDA encourages sponsors to enroll patients across disease stages and phenotypes.  Data from 
even a relatively small number of patients across different disease subgroups may help to support 
an indication that includes broader groups of patients.  In general, FDA will consider approval 
for a broader patient population unless issues (e.g., an unacceptable safety risk, an expected lack 
of effectiveness in certain subpopulations) exist that provide arguments against such an 
approach. 
 
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