Cellular Therapy for Cardiac Disease: Guidance for Industry | Guideline Explorer

Description

We, FDA, are issuing this guidance to provide you, sponsors who are developing cellular therapies for the treatment of cardiac disease, with recommendations on the design of preclinical1and clinical studies, and on the chemistry, manufacturing, and controls (CMC) information to include in an Investigational New Drug application (IND) for cellular therapy for cardiac disease. This guidance also provides recommendations regarding the information that you should submit on the product’s delivery system. Sponsors should consult with FDA concerning the regulatory pathway for the use of cell selection devices.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

5

Cellular Therapy

Additional considerations may exist for cellular therapies.

Cellular product

The material delivered by the system.

Cellular therapies

Excluded from the scope of this guidance

Drug-eluting coronary stent

potential impact on viability and activity of cellular product

Combination Product

Products combining drug, device, or biological constituents; Generally recommended for Enhanced Documentation; Requires 14971-based framework incorporating ICH Q9; A drug-device combination where the device constituent part detects ingestion.

Stakeholders

4

Sponsor

Entity responsible for submitting applications under section 524B

Institutional review boards

Standards for boards protecting human subjects.

Clinical events adjudication committee

independent body for Phase 3 studies

Interventional cardiologist

determines candidacy for percutaneous intervention

Regulatory Context

Regulatory Activities

8

Premarket Approvals

Source of safety information

Licensure

Requirement for biological products under the PHS Act

Phase 3 study

pivotal trials requiring clinically relevant primary endpoints

Special Protocol Assessment

repeat-dose toxicity studies that support a carcinogenicity Special Protocol Assessment (SPA)

510(k) premarket notifications

Source of safety information

Investigational New Drug application

Required for products more than minimally manipulated or for other indications.

IND

Investigational New Drug submissions

IDE

Investigational Device Exemption submissions; Submission Documentation for Investigational Device Exemptions; Investigational Device Exemption submission recommendations

Document Types

8

Master Files

Draft guidance regarding NDI notification master files.

Device labeling

Where maximum flow rate and turns to failure should be reported.

Test report

document that should include descriptions of motion characteristics used in testing

Informed consent document

must describe reasonably foreseeable risks

Statistical analysis plan

include the overall strategy for handling different intercurrent events... in the statistical analysis plan

Trial protocol

the rationale should be described in the trial protocol

Case report form

Standardized form recommended for data collection in clinical trials.; Documentation artifact for clinical trials

Master File

Documentation artifact related to NDI notifications

Attributes

9

Shelf Life

Determined based on stability data; Established through stability testing; also called dating period.; Established through formal stability studies; Establishing the period during which a drug product is expected to remain within specifications; Period for drug products; The period during which a drug product is expected to remain within specifications; Duration product remains within acceptance criteria; Period during which product remains within specifications; Established for intermediates pu

Buckling force

Force required to cause an undeflected catheter to buckle.

Stiffness

Flexibility of the complete device measured by deflection.

Intent-to-treat population

Primary analysis population for efficacy

New York Heart Association classification

categorization of heart failure severity

Cardiac ejection fraction

cutoff values used for study entry

Sterility assurance level of 1 x 10⁻⁶

Target level for device sterilization

Cell viability

Critical characteristic impacted by device interaction.

Biocompatibility

impact the biocompatibility of the device

Technical Details

Substances

1

Monoclonal antibodies

including monoclonal antibodies for prophylactic use

Testing Methods

10

In Vitro Testing

two years relevant experience with in vitro testing

Cable/Connector Separation Test

Determining reliability of mechanical or electrical connections.

Radiopacity assessment

Determining ability to observe the device using fluoroscopy.

Fatigue testing

Mechanical testing of a device.

Bond Strength testing

Characterizing resistance to tensile, bending, and torsional forces.

Burst pressure testing

Determining the pressure beyond which the device is expected to leak or rupture.

Dimensional verification

Ensuring device dimensions meet specifications.

Sensitivity analyses

Used to evaluate the robustness of overall survival results

Echocardiography

Method for measuring ejection fraction

Holter monitoring

Preferred modality for assessing effectiveness; used for screening atrial tachyarrhythmia recurrences

Processes

3

Sterilization

Required for contaminated equipment and media before disposal

In Vitro Testing

Testing performed under conditions simulating clinical use.

Immunomagnetic selection

common processing step for cellular products

Clinical Concepts

10

Cardiac Disease

treatment of cardiac disease; Target disease for the cellular therapy; Trials for the treatment of cardiac disease have the potential for bias

Adverse experiences

Reports of injuries resulting from battery failures

Symptomatic heart failure

patient population for recruitment

Refractory myocardial ischemia

patient population for recruitment

Refractory Angina

Subject population with refractory angina/ischemia; Subject population criteria for clinical trials

Acute Ischemia

Subject population with acute ischemia/infarction; patient population for recruitment

Heart Failure

Patient population for new indication

Arryhthmias

Monitoring for arryhthmias and conduction abnormalities

Myocardial Perforation

Monitoring for myocardial perforation/pericardial effusion

Myocardial infarction

For studies in which the outcome or outcomes of interest (e.g., myocardial infarction or stroke) include fatal outcomes.

Identified Hazards

Hazards

5

Tumorigenicity

Risk associated with intended pharmacology or off-target effects

Vessel dissection

Risk associated with excessive buckling force.

Vessel perforation

Inappropriately designed guidewire tips may result in vessel perforation

Humoral immune response

risk in subjects receiving allogeneic cells

Pericardial effusion

risk following product administration into the cardiac wall

Standards & References

External Standards

2

ACC/AHA guidelines

Evidence-based guidelines for optimal medical therapy

ANSI/AAMI ST72

Bacterial endotoxins – Test methods, routine monitoring, and alternatives

Specifications

2

Acceptance criteria

Metrics established by developers for each test element.

Burst pressure

Pressure limit the catheter body should withstand.

ICH References (4)

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.

ICH E8

General Considerations for Clinical Studies

ICH E6

Referenced for safety data collection and adverse event reporting plans.

Related CFR Sections (5)

21CFR50.25§ 50.25 Elements of informed consent.
(a) Basic elements of informed consent. In seeking informed consent, the following information shall be provided to each subject:Read full regulation →
21CFR312.32§ 312.32 IND safety reporting.
(a) Definitions. The following definitions of terms apply to this section:Read full regulation →
21CFR3.2§ 3.2 Definitions.
For the purpose of this part:Read full regulation →
21CFR3.4§ 3.4 Designated agency component.
(a) To designate the agency component with primary jurisdiction for the premarket review and regulation of a combination product, the agency shall determine the primary mode of action of the product. Where the primary mode of action is that of:Read full regulation →
21CFR312.23§ 312.23 IND content and format.
(a) A sponsor who intends to conduct a clinical investigation subject to this part shall submit an “Investigational New Drug Application” (IND) including, in the following order:Read full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Adulterated under section 501(f)(1)(B)

21

Misbranded under section 502(o)

19

Failure to establish and maintain procedures to control the design of the device

10

Failure to establish and maintain procedures for implementing corrective and preventive action

10

Failure to adequately develop, maintain, and implement written MDR procedures

10

Failure to establish and maintain procedures for receiving, reviewing, and evaluating complaints

8

Failure to adequately establish and maintain procedures for receiving, reviewing, and evaluating complaints

8

Failure to establish and maintain procedures for implementing corrective and preventive actions

8

Unapproved Device Violations

8

Failure to establish and maintain procedures for validating the device design

7

Recent Cases

Related Warning Letters (10)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics

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