Nonclinical Evaluation of Late Radiation Toxicity of Therapeutic Radiopharmaceuticals | Guideline Explorer

Description

The objective of this guidance is to provide recommendations to industry for designing nonclinical late radiation toxicity studies to determine potential late radiation effects of therapeutic radiopharmaceutical agents. The purpose of conducting nonclinical late radiation toxicity studies is to help minimize the risk of late-occurring radiation toxicities in clinical trials of therapeutic radiopharmaceuticals. Because there are other guidances available for conventional nonclinical safety studies, this guidance focuses solely on late radiation safety concerns that are unique to therapeutic radiopharmaceuticals. These unique safety concerns result from the risk of irreversible late radiation toxicity when these agents deliver high doses of ionizing radiation to normal organs.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

4

Therapeutic Radiopharmaceuticals

Agents that deliver high doses of ionizing radiation to normal organs; Nonclinical evaluation of late radiation toxicity for these agents

Diagnostic Radiopharmaceuticals

Low doses not expected to elicit late radiation toxic effects; Usually gamma emitters given in lower activities than therapeutic radiopharmaceuticals

Radiobiologicals

e.g., radiolabeled monoclonal antibodies

Therapeutic Radiopharmaceutical

A radiopharmaceutical drug product or radiobiological intended for use in the treatment of cancer in humans

Stakeholders

1

Sponsor

Entity responsible for submitting applications under section 524B

Regulatory Context

Regulatory Activities

4

Clinical Trials

The regulatory activity where inclusion of specific populations is discussed; The primary vehicle for generating robust clinical data for these populations.; Trials including pregnant participants for non-obstetric or obstetric indications; Inclusion of breastfeeding women in clinical trials; Research studies where breastfeeding women may be included.; The context in which these outcome parameters are collected.

Phase 2 Dose Escalation Clinical Trials

Studies should ideally be completed before the start of these trials

Phase 2 Dose Escalation Toxicity Trials

Initiated in patients after animal radiation toxicity studies are completed

Phase 1-2 Trials

Results of two trials involving 166Ho-DOTMP Plus Melphalan

Document Types

1

Radiation Toxicity Studies

Studies in animals that should be completed before phase 2 trials

Attributes

7

Tracer Dose

The lowest dose based on the as-low-as-reasonably-achievable principle

Tolerance Dose

The dose limit of an organ to minimize symptomatic late radiation toxicity

Pharmacokinetics

PK data used to evaluate drug pharmacology.

Biodistribution

Determines the dose received by each organ for systemically administered agents

NOAEL

No-observed adverse effect level for histological changes

Radiation Absorbed Dose

The energy imparted to matter by ionizing radiation per unit mass

Radiosensitivity

Relative susceptibility of cells, tissues, or organs to the injurious action of radiation

Technical Details

Substances

5

Cold Formulation

Nonradioactive drug substance used as a control group

166Ho-DOTMP

Used plus Melphalan in patients with Multiple Myeloma

Melphalan

Used in combination with 166Ho-DOTMP

Yttrium 90-DOTATOC

Internal radiotherapy causing Renal Thrombotic Microangiopathy

Angiotensin II Receptor Antagonists

Used in the treatment and prevention of radiation nephropathy

Testing Methods

4

Nonclinical Late Radiation Toxicity Studies

Studies designed to determine potential late radiation effects

Histopathology

The standard of truth for measuring diagnostic performance.; Typically used as a truth standard for optical imaging drugs.

Human Dosimetry

Data using tracer doses should be obtained before nonclinical study initiation

Histopathologic Evaluation

Detailed microscopic evaluation performed at study termination

Processes

5

External Beam Radiotherapy

Comparison of radiation absorbed doses with radiopharmaceuticals

Nonclinical Late Radiation Toxicity Studies

Conducted to identify organs at risk and establish a margin of safety

Radiopharmaceutical Therapy

Prescribing individualized doses to patients based on tolerance doses

Dose Fractionation

A method of administering therapeutic radiation in which relatively small doses are given daily or at longer intervals

Peripheral Blood Stem Cell Transplantation

Followed by 166Ho-DOTMP Plus Melphalan in patients with Multiple Myeloma

Clinical Concepts

10

Late Radiation Toxicity

Irreversible toxicity occurring after high doses of ionizing radiation; Irreversible toxicities in kidneys and bladder observed in clinical trials; Evaluation of effects appearing 60 days or more following an acute exposure

Renal Failure

Goal to mitigate the risk of renal failure

Pulmonary Failure

Late radiation toxicity associated with XRT and radiopharmaceuticals

Bone Marrow Failure

A potential long-term or delayed onset toxicity of RPTs.

Thrombotic Microangiopathy

Severe condition (TMA) requiring renal dialysis in clinical trials

Acute Radiation Toxicity

Injury appearing within days to weeks, often self-limiting and reversible

Acute Radiation Syndrome

Clinical manifestations resulting from exposure to high doses of radiation; The primary disease state discussed in the guidance.; appropriate for the ARS subsyndrome

Multiple Myeloma

Specific hematologic cancer type; use of MRD as a potential surrogate endpoint to expedite drug development; MM

Renal Thrombotic Microangiopathy

A new cause identified as Yttrium 90-DOTATOC internal radiotherapy

Radiation Nephropathy

Treatment and prevention using Angiotensin II Receptor Antagonists

Identified Hazards

Hazards

1

Radiation Damage

Modification in the canine kidney by hyperthermia

Standards & References

External Standards

1

External Beam Tolerance Dose Limits

Used to estimate administered doses in radiopharmaceutical trials

Specifications

2

Radiation Absorbed Dose

Estimated dose to specific tissue or organs

23 Gray

Radiation tolerance dose for the kidneys in conventionally fractionated XRT

ICH References (2)

ICH M3(R2)

Guidance on when particular studies can be abbreviated or deferred for life-threatening diseases

ICH S6

Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure of the study director to assure protocol compliance and accurate data recording

1

Failure of the study director to assure experimental data are accurately recorded and verified

1

Failure to properly identify specimens

1

Failure to assure experimental data were accurately recorded and verified

1

Failure to authorize and document deviations from standard operating procedures

1

QAU failed to assure reported results accurately reflect raw data

1

Failure to maintain a Quality Assurance Unit

1

Study director failed to assure protocol compliance and data accuracy

1

Fabrication of animal weight data

1

Failure to establish procedures for handling test and control articles

1

Recent Cases

Related Warning Letters (9)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics

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