Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment Guidance for Industry | Guideline Explorer

Description

This guidance addresses FDA’s 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. 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).

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

3

Drugs

Clinical investigations of drugs, including human drugs and biological products

Companion Diagnostic Device

Device protocols excluded from SPA

Dystrophinopathy-specific drugs

FDA could approve a drug for dystrophinopathies if a specific beneficial effect on the nervous system were demonstrated

Stakeholders

2

Regulatory Context

Regulatory Activities

2

Accelerated Approval

Pathway for drugs and biologics for serious conditions; Regulatory pathway supported by surrogate or intermediate endpoints; Regulatory pathway based on surrogate or intermediate endpoints; Pathway for products based on surrogate or intermediate clinical endpoints

Marketing Approval

Confirmatory studies intended to provide an adequate basis for approval

Document Types

1

Labeling

Cybersecurity information should be included in device labeling

Attributes

3

Analytical validity

Supported by data to show the test performs as intended.

Benefit-Risk

Considerations for the overall assessment of the drug's profile.

Genotype

Important baseline and prognostic variable for matching control groups.

Technical Details

Substances

3

Dystrophin protein

genetic mutations in the dystrophin gene that decrease the amount of dystrophin protein

biomarkers

Results involving biomarkers collected in the studies for efficacy and safety

Dystrophin

Immune responses to dystrophin are adverse events of special interest.; Dystrophin is expressed in the brain

Testing Methods

10

Randomized Placebo-Controlled Trials

Most efficient way to demonstrate efficacy.

Carcinogenicity studies

Evaluation of hydrogen peroxide safety

Juvenile animal studies

Nonclinical toxicity testing in young animals

Magnetic resonance spectroscopy

consider the use of other biomarkers, such as those measured with magnetic resonance spectroscopy

Patient-Reported Outcomes

Examples of COAs including work productivity

Genotyping

Baseline laboratory assessment for patient enrollment.

6-minute walk test

Measurement of physical function

2-minute walk test

shorter versions such as the 2-minute walk test

Myometry

As with myometry, sponsors should support the clinical meaningfulness

Echocardiography

Method for measuring ejection fraction

Processes

4

Pharmacokinetic/Pharmacodynamic Considerations

Trials should include assessment of PK and the relationship between drug exposure and virologic success.

Prognostic Enrichment

Use of inclusion criteria to select patients with characteristics that predict rapid decline.

Predictive Enrichment

Direct therapy to patients with a particular disease characteristic.

Stratified randomization

increased through stratified randomization based on one or more prognostic factors

Clinical Concepts

10

Duchenne muscular dystrophy

most common and generally most severe dystrophinopathy; Serious and life-threatening nature of DMD.; serious and life-threatening nature of diseases such as DMD; Document title and primary disease focus

subpopulations

Expected lack of effectiveness in certain subpopulations

efficacy

Biomarkers collected in the studies for efficacy

primary and secondary endpoints

sponsors analyze the primary and secondary endpoints as continuous or ordinal variables.

Dystrophinopathies

Related disease states discussed in the guidance

Chronic heart failure

Evidence of effectiveness in chronic heart failure has traditionally relied on randomized trials

Becker muscular dystrophy

characterized by wide interpatient variability in severity

DMD-associated dilated cardiomyopathy

caused by dystrophin mutations that primarily affect cardiac muscle

Symptomatic carrier states in females

female carriers of dystrophin mutations experience muscle degeneration

Adverse Events of Special Interest

Specific adverse events requiring justification in Section 9.2.4; Events of scientific and medical concern relative to the trial intervention.; Safety outcomes to be analyzed in the protocol

Identified Hazards

Hazards

2

Exacerbation of cardiac disease

Concern for drugs that increase physiological stress on the heart.

unacceptable safety risk

Issues that provide arguments against a broader patient population approval

ICH References (2)

ICH E9

Statistical Principles for Clinical Trials; Discourages deterministic procedures due to high risk of bias; Notes that the use of Bayesian methods in clinical trials may be considered.

ICH E10

Choice of Control Group in Clinical Trials.

Related CFR Sections (4)

21CFR312.42§ 312.42 Clinical holds and requests for modification.
(a) General. A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or more of the investigations covered by an IND. When a proposed study is placed on clinical hold, subjectRead full regulation →
21CFR312.80§ 312.80 Purpose.
The purpose of this section is to establish procedures designed to expedite the development, evaluation, and marketing of new therapies intended to treat persons with life-threatening and severely-debilitating illnesses, especially where no satisfactory alternative therapy exists. As stated § 314.10Read full regulation →
21CFR314.125§ 314.125 Refusal to approve an NDA.
(a) The Food and Drug Administration will refuse to approve the NDA and for a new drug give the applicant written notice of an opportunity for a hearing under § 314.200 on the question of whether there are grounds for denying approval of the NDA under section 505(d) of the Federal Food, Drug, and CoRead full regulation →
21CFR314.105§ 314.105 Approval of an NDA and an ANDA.
(a) FDA will approve an NDA and send the applicant an approval letter if none of the reasons in § 314.125 for refusing to approve the NDA applies. FDA will issue a tentative approval letter if an NDA otherwise meets the requirements for approval under the Federal Food, Drug, and Cosmetic Act, but caRead full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure to obtain informed consent

5

Failure to ensure that the investigation was conducted according to the investigational plan

3

Failure to submit an Investigational New Drug application (IND)

2

Failure to ensure proper monitoring of the investigation

1

Failure to submit an IDE application and obtain FDA approval

1

Failure to secure clinical investigator's compliance

1

Failure to immediately conduct an evaluation of unanticipated adverse device effects

1

Failure to obtain permission from the subjects' parent or guardian

1

Failure to review proposed research at convened meetings with a majority of members present

1

Failure to prepare and maintain adequate documentation of IRB activities, including minutes of IRB meetings

1

Recent Cases

Related Warning Letters (10)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics

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