BY PHASE


Nuclear Medicine

DRUG DISCOVERY AND DEVELOPMENT: RADIOPHARMACEUTICALS FOR THERAPEUTIC USAGE

Investigational New Drug Application (IND) and Exploratory IND (eIND)

  • If the compound, labeled or unlabeled, has never been previously administered to humans, the US FDA requires an Investigational New Drug (IND) Application.
  • Whether an exploratory IND (eIND) or a full IND needs to be submitted, depends on the mass of drug administered.
    1. — If the administered dose complies with the definition of a microdose, i.e. “less than 1/100th of the dose of a test substance calculated (based on animal data) to yield a pharmacological effect to the substance, with a maximum dose of ≤100 µg or in, the case of biologics, ≤ 30 nanomoles”, an exploratory IND submission is supported, which requires reduced preclinical safety and toxicology testing.

Radioactive Drug Research Committee (RDRC)

  • For radiolabeled compounds which have been used in humans before, and for which there is no intent to commercialize, approval from the “Radioactive Drug Research Committee” (RDRC) is considered sufficient to initiate clinical research studies.
  • The RDRC assesses the pharmacological and radiation dose administered in a clinical study. This usually requires whole-body dosimetry estimation in e.g. non-human primates, prior to initiating a phase 0 PET microdosing study.

Pharmacology and toxicological information

  • Adequate information about pharmacological and toxicological studies of the drug involving laboratory animals or in vitro, on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations.
  • The kind, duration, and scope of animal and other tests required varies with the duration and nature of the proposed clinical investigations.

Clinical adverse event data

Radiation Safety Assessment

  • Must establish the radiation dose by radiation dosimetry evaluations in humans and appropriate animal models.
  • The maximum tolerated dose need not be established.

Purpose

  • Aid in identifying at-risk organs.
  • Establish a margin of safety for late radiation toxicity.
  • Quantify potential organ sparing when dose fractionation is used.
  • Compare organ tolerance doses for radiopharmaceutical therapy to the published tolerance doses for conventionally fractionated high dose rate radiotherapy.

Study timing

• Should ideally be completed and analysed before phase 2 dose escalation toxicity trials are iniated in patients.

Species

• The most appropriate species is chosen based on human dosimetry and pharmacokinetic data using tracer doses.

Dosing Schedule

• It should mimic the anticipated clinical trials, in terms of amount of injected radioactivity, number and frequency of doses, and dosing interval.

Doses

  • At least four dose levels to produce no, mild, moderate, and severe late radiation toxicity.
  • Include cold formulation control (equivalent to the highest mass dose) to distinguish radiation from pharmacological effects.
  • Express doses as radiation absorbed dose to the critical organs.

Duration

• Animals should be monitored for late radiation toxicity for at least 1 year after dosing.

The Clinical Trials Directive 2001/20/EC, Article 2 (d), provides the following definition for an Investigational Medicinal Product (IMP):

“a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorization but used or assembled (formulated or packaged) in a way different from the authorized form, or when used for an unauthorized indication, or when used to gain further information about the authorized form.”

Radiopharmaceuticals which may be classified as IMPs include radiolabelling kits, radionuclide generators and radionuclide precursors.

The following are NOT considered to be IMPs:

  1. Any medicinal product prepared in a pharmacy in accordance with a medical prescription for an individual patient (“magistral formula”).
  2. Any medicinal product which is prepared in a pharmacy in accordance with the prescriptions of a pharmacopoeia and is intented to be supplied directly to the patients served by the pharmacy in question (“officinal formula”).
  3. Medicinal products intended for research and development trials (i.e. not for diseases diagnosis or treatment).
  4. Intermediate products intended for further processing by authorized manufacturer.
  5. Any radionuclides in the form of sealed sources.
  6. Whole blood, plasma or blood cells of human origin, except for plasma which is prepared by a method involving an industrial process.
  7. Any advanced therapy medicinal product which is prepared on a non-routine basis according to specific quality standards under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient.

Medicinal products used in clinical trials but which are not the subject of the clinical trial, are also classified as non-investigational medicinal products.

  • Concomitant and rescue/escape medication (e.g. patient-controlled IV morphine for pain),
  • Challenge agents (e.g. methacoline bronchospasm challenge),
  • Tools to assess a relevant clinical trial endpoint (e.g. PET radiopharmaceutical to measure primary endpoint effect of an IMP on organ function).

Safety documentation requirements for radiopharmaceuticals

  • Information on effects of free radio-nuclide in the patient (due to poor radiolabeling efficiency or in vivo dissociation of the radio-labeled conjugate).
  • Information on occupational hazards, i.e. radiation exposure to hospital staff and environment.
  • Information on chemical toxicity and disposition of the ‘cold’ nuclide.
  • Mutagenicity studies on the radionuclide are not considered to be useful,

Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals

  • Includes recommendations on “micro-dose” nonclinical safety studies which may be applicable to radiopharmaceuticals.
  • Pre-clinical date requirements are less stringent than normal when a “micro-dose” approach is used.

 

Clinical

Non clinical

Dose to be Administered

Start and Maximum Doses

Pharmacology

General Toxicity

Studies

Genotoxicity

Approach 1:

 

Total dose ≤ 100 µg (no inter-dose interval limitations)

 

AND

 

Total dose ≤1/100th  NOAEL and ≤ 1/100th pharmacologically active dose (scaled on mg/kg for IV and mg/m2 for oral)

Maximal and startling dose can be the same but not exceed a total accumulated dose of 100 µg.

In vitro target/receptor profiling should be conducted.

 

Appropriate characterization of primary pharmacology mode of action and/or effects) in a pharmacodynamically relevant model should be available to support human dose selection.

Extended single dose toxicity study in one species, usually rodent, by intended route of administration with toxicokinetic data, or via the IV route. A maximum dose of 1000-fold the clinical dose on a mg/kg basis for IV and mg/m2 for oral administration can be used.

Genotoxicity studies are not recommended, but any studies or SAR assessments conducted should be included in the clinical trial application.

 

For highly radioactive agents (e.g., PET imaging agents), appropriate PK and dosimetry estimates should be submitted.

Approach 2

 

Total cumulative dose ≤500 µg, maximum of 5 administrations with a washout between doses (6 or more actual or predicted half-lives)

 

AND

 

each dose ≤100 µg

 

AND

 

each dose ≤ 1/100th of the NOAEL and ≤ 1/100th of the pharmacologically active dose.

Maximal daily and starting doses can be the same, but not exceed 100 µg.

In vitro target/receptor profiling should be conducted.

 

Appropriate characterization of primary pharmacology (mode of action and/or effects) in a pharmacodynamically relevant model should be available to support human dose selection.

7-day repeated-dose toxicity study in one species, usually rodent, by intended route of administration with toxicokinetic data or via the IV route. Hematology, clinical chemistry, necropsy, and histopathology data should be included. A maximum dose of 1000-fold on a mg/kg basis for IV and mg/m2 for oral administration can be used.

Genotoxicity studies are not recommended, but any studies or SAR assessments conducted should be included in the clinical trial application.

 

For highly radioactive agents (e.g., PET imaging agents), appropriate PK and dosimetry should be estimated.

Approach 3

 

Single Dose Studies at Sub-therapeutic Doses or into the Anticipated Therapeutic Range.

Starting dose should be based on the types of toxicity findings observed in the most sensitive species and a consideration of the pharmacologically active dose. For other considerations on initial dosing in humans, regional guidance should be consulted.

 

Maximum dose can be that yielding up to ½ NOAEL exposure in the more sensitive species, in cases where any relevant toxicity observed in animals is anticipated to be monitorable and reversible in humans.

In vitro target/receptor profiling should be conducted.

 

Appropriate characterization of primary pharmacology (mode of action and/or effects) in a pharmacodynamically relevant model should be available to support human dose selection.

 

Core battery of safety pharmacology.

Extended single dose toxicity studies in both the rodent and non-rodent by intended clinical route of administration with toxicokinetics, hematology, clinical chemistry, necropsy, and histopathology data.

Ames assay (or an alternative assay if Ames is inappropriate).

 

Clinical Trials for Nuclear Medicine

Phase 1

  • Single-dose studies, repeated/multiple dose studies (lasting no more than 28 days)
    • Typically conducted in 20 to 80 healthy subjects.
  • Studies assess safety and tolerance, pharmacokinetics, pharmacodynamics, bioavailability, bioequivalence and drug interaction.

    Phase 2

  • Early safety and efficacy studies
    • Up to 200 subjects with relevant disease.
    • Different potential indications and dose regimens may be studied.
  • The general goals of phase 2 studies include:
    • Refining the agent’s clinically useful mass dose and radiation dose ranges or dosage regimen (e.g., bolus administration or infusion)
    • Answering outstanding pharmacokinetic and pharmacodynamics questions.
    • Providing preliminary evidence of efficacy.
    • Expanding the safety database.
    • Optimizing the techniques and timing of image acquisition.
    • Developing methods and criteria by which images will be evaluated.
    • Evaluating other critical questions about the medical imaging agent.
  • Phase 3

  • Pivotal safety and efficacy studies
    • Active/placebo controlled.
    • Possibly randomized.
    • Hundreds to thousands of subjects
    • Two adequate and well-controlled studies providing independent confirmation of efficacy are typically required for NDA (or sNDA) filing.
  • The general goals of phase 3 studies include:
    • Confirming the principal hypotheses developed in earlier studies.
    • Demonstrating the efficacy of the medical imaging agent.
    • Demonstrating the continued safety of the medical imaging agent.
    • Validating instructions for use and for imaging in the population for which the agent is intended.
  • DRUG DISCOVERY AND DEVELOPMENT: RADIOPHARMACEUTICALS FOR DIGITAL IMAGING

    Overview

    Characteristics of Radiopharmaceuticals for Digital Imaging Relevant to Safety

    1. Mass dose – some radiopharmaceuticals can be administered at low doses. For example, the mass dose of a single administration of a radiopharmaceutical can be small because device technologies can typically detect relatively small amounts of a radionuclide (e.g., radiopharmaceuticals for myocardial perfusion imaging). When a medical imaging is administered at a mass dose that is at low end of the dose-response curve, dose-related adverse events are less likely to occur.
    2. Route of administration - some radiopharmaceuticals are administered by routes that decrease the likelihood of systemic adverse events. For example, medical imaging agents that are administered as contrast media for radiographic examination of the gastrointestinal tract (e.g., barium sulfate) can be administered orally, through an oral tube, or rectally. In patients with normal gastrointestinal tracts, many of these products are not absorbed, so systemic adverse events are less likely to occur. In general, non-radiolabeled contrast agents pose safety issues similar to therapeutic drugs because of the inherently large amounts needed for administration. Therefore, non-radiolabeled drugs generally should be treated like therapeutic agents for the purpose of conducting clinical safety assessments.
    3. Frequency of Use – both contrast and diagnostic pharmaceuticals, are administered infrequently as or as single doses. Accordingly, adverse events that are related to long-term use or to accumulation are less likely to occur with these agents than with agents that are administered repeatedly to the same patient. Therefore, the nonclinical development programs for such single-use products usually can omit long-term (i.e., 3 months’ duration or longer), repeat-dose safety studies.
    4. Biological, Physical, and Effective Half-Lives – radiopharmaceuticals often used radionuclides with short physical half-lives or that are excreted rapidly. The biological, physical and effective half-lives of diagnostic radiopharmaceuticals are incorporated into radiation dosimetry evaluations that require an understanding of the kinetics of the distribution and excretion of the radionuclide and its mode of decay.

    Performance of Nonclinical Safety Assessments

    1. Nonclinical Safety Assessments for Non biological Drug Products
      1. Timing of Non clinical Studies Submitted to an IND Application

    The nonclinical studies be timed so that there is a timely conduct of clinical trials, including appropriate safety monitoring based on findings in non-clinical studies) and to reduce the unnecessary use of animals and other resources.

      1. Contrast Agents

    Non clinical safety evaluations of such drug products be made more efficient with the following modifications:

    • Long term (i.e., greater than 3 months), repeat-dose toxicity studies in animals usually can be omitted.
    • Long-term rodent carcinogenicity studies usually can be omitted.
    • Reproductive toxicology often can be limited to an evaluation of embryonic and fetal toxicities in rats and rabbit and to evaluations of reproductive organs in short-term toxicity studies.
      1. Diagnostic Radiopharmaceuticals (Non biological Products)
    • Long term, repeat-dose toxicity studies in animals typically can be omitted.
    • Long term rodent carcinogenicity studies typically can be omitted.
    • Reproductive toxicology studies can be waived when adequate scientific justification is provided.
    • Genotoxicity studies should be conducted on the nonradioactive component because the genotoxicity of the nonradioactive component should be identified separately from that of the radionuclide. Genotoxicity studies can be waived if adequate scientific justification is provided.
    1. Non clinical Safety Assessments for Biological Products

    Many biological products raise relatively distinct nonclinical issues such as immunogenicity and species specificity.

    Clinical Safety Assessments

    1. Group 1 and 2 Medical Imaging Agents

    Generally, a less extensive clinical safety evaluation is appropriate for Group 1 agents. Conversely, Group 2 agents undergo standard clinical safety evaluations in clinical trials throughout their development.

    1. Group 1 Medical Imaging Agents
      • The medical imaging agent meets either the safety-margin considerations or the clinical-use considerations.
      • The medical imaging agent is not a biological product.
      • The medical imaging agent does not predominantly emit alpha or beta particles.

    Medical imaging agents that are administered in low mass doses to human are considerably under Group I than those administered in higher mass doses. Important exceptions including cases where the medical imaging agents are likely to be immunogenic when the pharmacologic response exists at a low mass dose, or when the medical imaging agents cause adverse reactions that are not dose-related.

    1. Group 2 Medical Imaging Agents

    All biological products are assumed to be Group 2 agents unless the product lacks immunogenicity. Medical imaging agents that are biologically active in animal studies or in human studies when administered at dosages that are similar to those intended for clinical use is also under Group 2 agents.

    1. Considerations for Groups 1 and 2
    1. Safety – Margin Considerations
      1. Results of nonclinical studies
    • To be considered a Group 1 agent under the safety-margin considerations, a medical agent that have an adequately documented margin of safety as assessed in the nonclinical studies.
      • A NOAEL in expanded-acute, single-dose toxicity studies in suitable animal species be at least one hundred times greater than the maximal dose to be used in human studies.
      • A NOAEL in safety pharmacology studies in suitable species be at least one hundred greater than the maximal dose to be used in human studies.
      • A NOAEL in short-term, repeated-dose toxicity studies in suitable animal species be at least twenty-five times greater than the maximal mass dose to be used in human studies. Short-term, repeat-dose toxicity studies are conducted to evaluate the effects of exaggerated dose regimens.
        1. Results of initial human experience
    • Identification of any adverse events during initial human use that were not predicted form effects observed in animals could be considered significant, regardless of severity. If adverse events occur at any time during human studies, a risk assessment should be conducted to determine whether the medical imaging agent should be considered as a Group 2 medical imaging agent. The risk assessment will examine the type, frequency, severity, a potential attribution of the adverse events with respect to what is known about the pharmacology of the drug.
    • Human pharmacokinetic studies of the radiopharmaceutical be performed during phase 1 to collect information about the disposition of the radioactivity in human

    Design Features for Radiopharmaceutical Imaging Trials.

    The following elements should unambiguously described in the protocol:

    • Representative subject population
    • Clinically meaningful endpoints
    • Detailed imaging procedures
    • Procedures for independent blinded evaluations
      • Image interpretation
        • Two or more independent readers
          • Results typically presented by reader.
    • Standard of truth
    • Determinations provided without access to investigational imaging or other information that could introduce bias.

    FDA Guidance on Endpoints for Radiopharmaceuticals Imaging Trials

    Medical imaging agents can be developed for:

    1. Structural delineation
    2. Functional, physiological, or biochemical assessment
    3. Disease or pathology detection assessment
    4. Diagnostic or therapeutic patient management

    Categories of endpoints

    1. Image interpretations
    2. Objective image features
    3. Subjective image assessments
    4. Clinical outcomes

    Clinical Trial Endpoints

    Primary Endpoint

    • A measure that will permit the primary (or most important) question of the trial to be answered; e.g.
      1. If the primary objective is to determine whether a new imaging agent/application is superior to a current approved procedure, the primary endpoint might be the detection of a specific pathology expected to be identified by the two procedures.

    Secondary Endpoint

    • Measures that can be considered subsidiary to the primary objective of the trial but which are of potential clinical interest.
      1. A secondary endpoint might be the size of the lesion of the pathology of interest.
      2. This information might be useful for later assessment of the detection limit for the new procedure.

    Standard of Truth (SoT)

    • An accepted evaluation against which an investigational imaging procedure is compared.
      1. Biopsy when studying an agent used to distinguish malignant tumors from benign tumors.
      2. Approved contrast enhanced DSA when studying a contrast agent used for MR or CT angiography to detect stenosis or vessel blockages.
      3. Diagnosis by a movement disorder specialist when studying an agent for diagnosing early Parkinson Syndromes.
      4. Two-year outcome when studying an agent for assessing prognosis for a cardiac event such as myocardial infarction or sudden cardiac death.

    Comparator

    • An established imaging modality and/or agent to which the images from the new agent are compared for secondary endpoints.
    • If a definite standard of truth would be considered too dangerous or unethical (e.g. high complication rate from percutaneous biopsy to confirm a probable benign pathology), results from a highly reliable comparator may be accepted for primary endpoint analyses.
    • In many other circumstances, the comparator is not considered a truth standard and its results are also tested against the truth standard (e.g. both a new and an established MPI agent compared against coronary angiography for identification of CAD).