Radiation dosimetry study: preclinical and early phase clinical trials

Radiopharmaceutical clinical trials are highly complex. Regulatory agencies, such as the FDA and EMA, demand robust data for dosimetric evaluation for clinical trials. FDA CFR 21 states: “…sufficient data from animal or human studies to allow a reasonable calculation of radiation-absorbed dose to the whole body and critical organs upon administration to a human subject. Phase 1 studies of radioactive drugs must include studies which will obtain sufficient data for dosimetry calculations.” TRACER can inform and advise you on the preclinical necessities. Schedule a meeting with us to discuss the (pre)clinical steps to bring your radiopharmaceutical into clinical trials as fast as possible.

Regulations on clinical trials for radiopharmaceuticals

For translational clinical trials, the harmonized regulations ICH M3 guideline provides guidance on non-clinical safety studies. It lists the required toxicology studies for pharmaceuticals, including radiopharmaceuticals. Listed below are several other regulatory documents of importance. Ahead of your conversation with TRACER, you can already check the following resources.

1. EANM guidance document: dosimetry for first-in-human studies and early phase clinical trials
2. SNMMI MIRD Pamphlet 11, which can be found in all MIRD material
3. EMA Radiopharmaceuticals – Scientific guideline
4. EMA Clinical evaluation of diagnostic agents – Scientific guideline
5. EMA Guideline on the non-clinical requirements for radiopharmaceuticals
6. FDA Microdose Radiopharmaceutical Diagnostic Drugs: Nonclinical Study Recommendations
7. FDA Nonclinical Evaluation of Late Radiation Toxicity of Therapeutic Radiopharmaceuticals
8. FDA Oncology Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations Guidance for Industry

Different requirements on dosimetry studies for diagnostics and therapeutics

Regulators divide radiopharmaceuticals for diagnostics and therapeutics. Diagnostic radiopharmaceuticals have fewer preclinical requirements than therapeutic radiopharmaceuticals. Drug developers are always required to evaluate the toxicity, estimate absorbed radiation dose, and justify the efficacy-potential of the radionuclide and ligand or carrier component. To do so, accurate measurement of the radiation dose absorbed by tissue and organs is required. A combination of imaging, bioassays, and calculations via software are included in these clinical trials.

Clinical trial documentation for radiopharmaceuticals

The clinical trial submission documentation for radiopharmaceuticals should include data on chemical and pharmaceutical properties, production, radioactive characteristics, safety, efficacy, toxicology, and dosimetry. Preclinical toxicity studies may be omitted for no-carrier radioactive components for which toxicity is known. This data is needed in for example the Investigational Medicinal Product Dossier (IMPD), Clinical Trial Application (CTA), Investigator Brochure (IB), and Investigational New Drug Application(IND). Schedule a meeting if you need to discuss what applies to your clinical trial. We can help you prepare, write, or review documentation to start your clinical trial as soon as possible.

When data is already available on your radionuclide and ligand, your preclinical trajectory may be abbreviated. The first in human dose may be based on previous data. Relevant organ-specific data from published animal or human studies should be described. General toxicity studies may be omitted for the radionuclide only (without ligand). A general toxicology study in one species (same as biodistribution and dosimetry study) to evaluate ligand-induced toxicity can be conducted with the non-radioactive pharmaceutical.

The amount of non-clinical supporting data may be lower for diagnostics. Regulators deem the potential for adverse events unlikely when the dose is low enough. Typically, a microdose (≤ 100 µg) – similar to that used in Phase 0. Chronic toxicity studies may be omitted for the non-radioactive pharmaceutical (precursor) when dosing is limited to 2-3 times (with complete wash-out of the radiopharmaceutical before the next administration takes place), a microdose is administered, and the ligand is only for delivery. Drug developers should justify their decision to waive specific preclinical studies.

Genotoxicity, reproductive toxicology, and carcinogenicity studies may be omitted since the effect is evident for radiopharmaceuticals. Product labeling should include these warnings. When effects related to the above studies have been witnessed during (animal) studies, this should be described. For radiopharmaceuticals information regarding contraception for both men and women should be included. The same applies for lactating women to prevent or limit radiation exposure to the child.

Besides toxicity studies for exposure to the ligand, long term toxicity studies may be necessary to investigate the toxicity induced by exposure to radionuclides. Radiation-induced toxicity can lead to delayed or accumulated adverse events. Long term toxicity studies are important for treatments for patients with a long-life expectancy. A long-term radiotoxicity study may be done in a single-species animal study. Microscopic research is necessary for organs with significant pathology findings. A summary of animal distribution studies, human dosimetry studies, and publications on late radiation effects might also be sufficient. The FDA provides guidance on this subject.

The study of dosimetry comprises the measurement of a radioactive dose delivered and absorbed by organs and tissue. In the medical field, dosimetry studies are part of treatment and are an aspect of clinical trials for new therapies and diagnostics.

Dosimetry in radiopharmaceuticals evaluates the safety and efficacy of the radiopharmaceutical. One of the objectives of a dosimetry study is to find the optimal radioactivity dose. Analysis can be done with imaging techniques, such as PET and SPECT, and blood and urine samples. The radioactive dose absorbed by organs and tissue is calculated. In a dosimetry study, calculations are cross-checked with safety parameters such as hematology and blood chemistry measurements for radiotoxicity.

Internal dosimetry in nuclear medicine comprises the measurement of radiation in the body from a radiopharmaceutical. Internal dosimetry is studied in clinical trials for novel diagnostics and therapeutics. The biodistribution of a radionuclide is translated to organ and tissue exposure. With the advancements in radiopharmaceuticals for treatment, patient-specific dosimetry has become more important. Part of internal dosimetry is evaluating the distribution and kinetics of a radiopharmaceutical within individual patients.

In radiopharmaceuticals, alpha, beta, gamma, and Auger electron-emitters are used. Alpha and beta are used in therapy. Alpha decay is considerably stronger than beta decay but with a much shorter path length. Alpha and beta emitters may also release gamma rays. Gamma is only used for diagnostics. Auger is the least frequently used in clinical trials.

The amount of radiation delivered to organs and tissue can cause irreversible damage. In the case of oncology treatment, the killing of cancerous cells is intended. Dosimetry is important in nuclear medicine since it’s a fine line between effective treatment and severe side effects. Treatment would not achieve the desired effect when the dose is too low. But, when dosing is too high, side effects can be considered unacceptable. Preclinical studies and clinical trials aim to evaluate the efficacy and find the optimal dose.

MIRD stands for Medical Internal Dose Committee. The MIRD dosimetry method was presented in 1968 by the Society of Nuclear Medicine and serves as a standard in dosimetry. This method is a simplified model of the human body to evaluate radiation absorption in organs and tissues. It uses the physical half-life of the radionuclide and the biological half-life of the radiopharmaceutical in the body.

External dosimetry measures the radiation from a source outside the body. Measurements can be achieved with a dosimeter. For example, for personnel working with radioactivity and in radiation oncology. Internal dosimetry measures the radiation from a source inside the body. This is more complex because many factors have an influence on the absorbed dose in organs and tissues.

Clinical dosimetry, also known as medical dosimetry, refers to the patient-centered dosimetry tasks. It involves radiation treatment planning, dose calculation, and safety assurance. A clinical physicist or medical dosimetrist works in the clinic and adjusts the dose to specific patients. This is based on, among others: size, body weight, and vulnerability.

Radiopharmaceuticals are used in research to study biological processes. Examples are PET and SPECT imaging. TRACER utilizes these imaging methods in clinical trials to assess also non-radiopharmaceutical drugs. By labeling a drug with a radioactive tracer, the biodistribution and pharmacokinetics can be studied. Furthermore, imaging allows us to determine biological processes and characteristics in-vivo. We can identify biomarkers, receptors, genes, activities, and processes. Drug developers can increase their chances of success in clinical trials by an improved understanding of their drug and target.

Without going into too much detail, dosimetry studies are based on the source of the radiation and the receiving organs and tissue. Each uses its unit of measurement.

1. The energy emitted from the radionuclide – the number of nuclei decayed per second – is measured in Becquerel (Bq).
2. The Linear Energy Transfer (LET) describes the units of energy per unit distance in kiloelectron Volt (keV) per micrometer (μm).
3. The biological impact of the dose received by organs and tissue is measured in Sievert (Sv).
4. The energy absorbed is expressed in a unit named Gray (Gy).

There are different types of dosimetry.

• Internal and external dosimetry
• Microdosimetry and macrodosimetry
• Active and passive dosimetry
• Personalised and standard dosimetry

Below we compare and provide basic information on the commonly used distinctions.