Clinical Trial Imaging Endpoint Process Standards Guidance for Industry | Guideline Explorer

Description

The purpose of this guidance is to assist sponsors in optimizing the quality of imaging data obtained in clinical trials intended to support approval of drugs and biological products. This guidance focuses on imaging acquisition, display, archiving, and interpretation process standards that we regard as important when imaging is used to assess a trial’s primary endpoint or a component of that endpoint.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

3

Drug

Defined in section 201(g) of the FD&C Act; Articles intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease; Product classification based on chemical action or specific intended uses like altering pH

Biological Product

Regulated under section 351(i) of the PHS Act; Virus, therapeutic serum, toxin, vaccine, or protein applicable to prevention or treatment; Alternative regulation category for products meeting device definition

Diagnostic Imaging Drug

considerations involving the development of diagnostic imaging drugs

Stakeholders

6

Sponsor

Entity responsible for submitting applications under section 524B

Site investigator

Person responsible for archiving imaging information at the clinical site

Regulatory Context

Regulatory Activities

8

Phase 3 Trial

Sponsors should conduct two randomized, double-blind, controlled trials.

Biologics License Applications

BLA application type eligible for reduced fees.

New Drug Applications

Drug approval process under section 505 of the FD&C Act.

Audits

Clinical trial-related audits enabling verification of source data.

Inspection

FDA verification of qualified facility status, including for-cause inspections

Investigational device exemption

A submission required for clinical studies of certain medical devices.

Special Protocol Assessment

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

End-of-Phase 2 Meeting

Timeline trigger for iPSP submission

Document Types

10

Imaging Charter

detailed imaging process standards detailed in an imaging charter; A document that details trial-specific imaging process standards.; A document or series of documents describing clinical trial imaging methodology; Document describing imaging interpretation, data locking, and quality control processes; document fidelity to the charter-specified process

Final report

required as part of the premarket submission

Statistical Analysis Plan

Document for protocol execution; The sponsor should develop a statistical analysis plan that is consistent with the trial protocol; Deviations from this plan must be justified

Case report form

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

Case report forms

standardized formats aligned with the format of information collected in case report forms

Reader training manuals

Reader training manuals are key documents that contain more details of the reader training procedures.

Site imaging manuals

such information is included in site imaging manuals

Charter

Sponsors should draft charters that standardize procedures

Clinical Protocol

The template defines the structure and content of clinical protocols; The document provides a template for clinical electronic structured harmonised protocols; Ensure alignment with every other section of the protocol.; The primary document being structured and amended.

Clinical Trial Imaging Endpoint Process Standards Guidance for Industry

The title of the guidance document providing standards for imaging endpoints.

Attributes

7

Imaging Process Variability

minimization of imaging process variability may enhance detection of drug effects

Image annotations

some may involve image annotations before this transfer

Inter-reader performance

Metric comparing performance between different readers

Intra-reader variability

Proximity of readings in two modalities minimizes this

Uninterpretable

Criteria for classifying an image as uninterpretable based on a technical failure.

X-ray energy (kVp)

Technical parameter that must be standardized for breast imaging

Treatment Effect

Description of the treatment effect of interest.; The effect being measured and understood via supplementary analysis.; Assumption used in sample size calculation

Technical Details

Substances

3

Contrast Agents

Materials used during device-associated procedures

Radiopharmaceutical agents

commonly produced at clinical sites, and the quality of these drugs may vary

Iodinated Contrast Agent

Used within the heart during arteriography

Testing Methods

10

Dynamic Cardiac Arteriography

Used to assess coronary artery disease

Caliper-based lesion measurement

documented caliper-based lesion measurement

Pilot reading studies

Studies to test the reading and image lock process before Phase 3

Computer-assisted image interpretation

Computer-assisted image interpretation may form an important component of the read process.

Positron Emission Tomography

Source of radiological data

X-ray

Potential bone age assessments include imaging

Bone Mineral Density

variability across sites in bone mineral density

Echocardiography

Method for measuring ejection fraction

Single Photon Emission Computerized Tomography

An example of an imaging modality choice.

Computed Tomography of the Chest

Used in the National Lung Screening Trial.

Processes

9

Imaging Acquisition

guidance focuses on imaging acquisition process standards

Image Acquisition

processes that took place during the conduct of the trial

Quality control

Monitoring compliance with image display and interpretation processes

Imaging data lock process

Process where no further modification of image assessment is allowed

Calibration

Required for critical equipment to maintain quality

Site qualification process

charter should address the process used to qualify clinical sites for trial participation

Image Interpretation

centralized image interpretation for an imaging-based primary endpoint; The process of reading and analyzing acquired images; The act of reviewing and assessing clinical trial images; transfer of imaging data for image interpretation

Quantitative Imaging

extracts additional information from medical images in the form of numerical values; Technical performance assessment of quantitative imaging functions

Site Qualification

Ongoing process to maintain control of imaging hardware and software at sites

Clinical Concepts

7

Primary Endpoint

The main outcome measure in a clinical trial

Sedation

Adverse reaction from CNS depressants

Arthritis

Objective manifestation of Lyme disease used in endpoint assessment.; Treatment failure manifestation in natural history studies

Coronary Artery Disease

Example disease prevalence used in reporting demographics.

Arthritic Diseases

Diseases where specialized image interpretation relies on centralized imaging.

Long Bone Fracture

An example of an indisputable outcome where medical practice standards may suffice.

Intracranial Hemorrhage

An example of an outcome readily determined with widely implemented imaging methods.

Standards & References

External Standards

4

DICOM

Digital Imaging and Communications in Medicine standard for PACS

RECIST

Response Evaluation Criteria in Solid Tumors used for assessing response rate

RECIST Guideline

Response Evaluation Criteria in Solid Tumors version 1.1

Phantoms

Phantoms can serve as a high-quality reference standard for which the ground truth is known

Related CFR Sections (4)

21CFR312.58§ 312.58 Inspection of sponsor's records and reports.
(a) FDA inspection. A sponsor shall upon request from any properly authorized officer or employee of the Food and Drug Administration, at reasonable times, permit such officer or employee to have access to and copy and verify any records and reports relating to a clinical investigation conducted undRead full regulation →
21CFR312.62§ 312.62 Investigator recordkeeping and record retention.
(a) Disposition of drug. An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. If the investigation is terminated, suspended, discontinued, or completed, the investigator shall return the unused supplies of the drug tRead full regulation →
21CFR312.57§ 312.57 Recordkeeping and record retention.
(a) A sponsor shall maintain adequate records showing the receipt, shipment, or other disposition of the investigational drug. These records are required to include, as appropriate, the name of the investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each such Read full regulation →
21CFR314.126§ 314.126 Adequate and well-controlled studies.
(a) The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation. The characteristics described in paragraph (b) of this section have been develRead full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

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

21

Failure to submit an Investigational New Drug application (IND)

9

Unapproved new drug

5

Failure to obtain informed consent

5

Misbranded drug

4

Failure to submit INDs for the conduct of clinical investigations

3

Failure to ensure proper monitoring of the investigation

3

Enrollment of subjects who do not meet eligibility criteria

3

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

3

Failure to prepare and maintain adequate and accurate case histories

2

Recent Cases

Related Warning Letters (10)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics

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