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Guidance for Industry (PDF version of this document)
U.S. Department of Health and Human Services June 2004 Clinical Medical Additional copies of this Guidance are available from:
Division of Drug Information
HFD-240 http://www.fda.gov/cder/guidance/index.htm or
Office of Communication, Training
and http://www.fda.gov/cber/guidelines.htm Mail: the Voice Information System at 800-835-4709 or 301-827-1800.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)
June 2004 Clinical Medical
Table of Contents
I. INTRODUCTION........................................................................................................... 1 II. SCOPE — TYPES OF MEDICAL IMAGING agents............................................ 2 A. Contrast Agents............................................................................................................. 2 B. Diagnostic Radiopharmaceuticals................................................................................... 2 III. GENERAL CONSIDERATIONS FOR SAFETY ASSESSMENTS OF MEDICAL IMAGING agents............................................................................................................... 3 A. Medical Imaging Agent Characteristics Relevant to Safety............................................. 3 1. Mass Dose...................................................................................................................... 4 2. Route of Administration................................................................................................... 4 3. Frequency of Use............................................................................................................. 4 4. Biological, Physical, and Effective Half-Lives................................................................... 5 B. Performance of Nonclinical Safety Assessments............................................................. 5 1. Nonclinical Safety Assessments for Nonbiological Drug Products....................................... 5 a. Timing of Nonclinical Studies Submitted to an IND Application........................................ 5 b. Contrast Agents............................................................................................................ 6 c. Diagnostic Radiopharmaceuticals (Nonbiological Products)............................................... 8 2. Nonclinical Safety Assessments for Biological Products..................................................... 8 IV. CLINICAL SAFETY ASSESSMENTS.......................................................................... 9 A. Group 1 and 2 Medical Imaging Agents......................................................................... 9 1. Group 1 Medical Imaging Agents..................................................................................... 9 2. Group 2 Medical Imaging Agents.................................................................................... 10 B. Considerations For Groups 1 or 2................................................................................ 11 1. Safety-Margin Considerations........................................................................................ 11 a. Results of nonclinical studies........................................................................................ 11 b. Results of initial human experience............................................................................... 13 2. Clinical Use Considerations........................................................................................... 14 C. Radiation Safety Assessment for All Diagnostic Radiopharmaceuticals........................ 14 1. General Considerations.................................................................................................. 14 2. Calculation of Radiation Absorbed Dose to the Target Organs or Tissues......................... 15 3. Maximum Radiation Absorbed Dose............................................................................... 16
Guidance for Industry[1] Developing Medical Imaging Drug and Biological Products Part 1: Conducting Safety Assessments
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
I. INTRODUCTION
This guidance is one of three guidances intended to assist developers of medical imaging drug and biological products (medical imaging agents) in planning and coordinating their clinical investigations and preparing and submitting investigational new drug applications (INDs), new drug applications (NDAs), biologics license applications (BLAs), abbreviated NDAs (ANDAs), and supplements to NDAs or BLAs. The three guidances are: Part 1: Conducting Safety Assessments; Part 2: Clinical Indications; and Part 3: Design, Analysis, and Interpretation of Clinical Studies.
Medical imaging agents generally are governed by the same regulations as other drug and biological products. However, because medical imaging agents are used solely to diagnose and monitor diseases or conditions as opposed to treat them, development programs for medical imaging agents can be tailored to reflect these particular uses. Specifically, this guidance discusses our recommendations on conducting safety assessments of medical imaging agents.
FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
A glossary of common terms used in diagnostic medical imaging is provided at the end of this document.
II. SCOPE — TYPES OF MEDICAL IMAGING agents
This guidance discusses medical imaging agents that are administered in vivo and are used for diagnosis or monitoring with a variety of different modalities, such as radiography, computed tomography (CT), ultrasonography, magnetic resonance imaging (MRI), and radionuclide imaging. The guidance is not intended to apply to the development of in vitro diagnostic or therapeutic uses of these agents.[2]
Medical imaging agents can be classified into at least two general categories, contrast agents and diagnostic radiopharmaceuticals.
A. Contrast Agents
As used in this guidance, a contrast agent is a medical imaging agent used to improve the visualization of tissues, organs, and physiologic processes by increasing the relative difference of imaging signal intensities in adjacent regions of the body. Types of contrast agents include, but are not limited to, (1) iodinated compounds used in radiography and CT; (2) paramagnetic metallic ions (such as ions of gadolinium, iron, and manganese) linked to a variety of molecules and microparticles (such as superparamagnetic iron oxide) used in MRI; and (3) microbubbles, microaerosomes, and related microparticles used in diagnostic ultrasonography. B. Diagnostic Radiopharmaceuticals
As used in this guidance, a diagnostic radiopharmaceutical is (1) an article that is intended for use in the diagnosis or monitoring of a disease or a manifestation of a disease in humans and that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons or (2) any nonradioactive reagent kit or nuclide generator that is intended to be used in the preparation of such an article.[3] As stated in the preamble to FDA's proposed rule on Regulations for In Vivo Radiopharmaceuticals Used for Diagnosis and Monitoring, the Agency interprets this definition to include articles that exhibit spontaneous disintegration leading to the reconstruction of unstable nuclei and the subsequent emission of nuclear particles or photons (63 FR 28301 at 28303; May 22, 1998).
Diagnostic radiopharmaceuticals are generally radioactive drug or biological products that contain a radionuclide that typically is linked to a ligand or carrier.[4] These products are used in nuclear medicine procedures, including planar imaging, single photon emission computed tomography (SPECT), positron emission tomography (PET), or in combination with other radiation detection probes.
Diagnostic radiopharmaceuticals used for imaging typically have two distinct components.
· A radionuclide that can be detected in vivo (e.g., technetium-99m, iodine-123, indium-111).
The radionuclide typically is a radioactive atom with a relatively short physical half-life that emits radioactive decay photons having sufficient energy to penetrate the tissue mass of the patient. These photons can then be detected with imaging devices or other detectors
· A nonradioactive component to which the radionuclide is bound that delivers the radionuclide to specific areas within the body.
This nonradionuclidic portion of the diagnostic radiopharmaceutical often is an organic molecule such as a carbohydrate, lipid, nucleic acid, peptide, small protein, or antibody. As technology advances, new products may emerge that do not fit into these traditional categories (e.g., agents for optical imaging, magnetic resonance spectroscopy, combined contrast and functional imaging). It is anticipated, however, that the general principles discussed here could apply to these new diagnostic products. Developers of these products should contact the appropriate reviewing division for advice on product development.
III. GENERAL CONSIDERATIONS FOR SAFETY ASSESSMENTS OF MEDICAL IMAGING agents
A. Medical Imaging Agent Characteristics Relevant to Safety
The following sections discuss the special characteristics of a medical imaging agent that can lead to a more focused safety evaluation. Characteristics include its radiation absorbed dose, mass dose, route of administration, frequency of use, biodistribution, and biological, physical, and effective half-lives in the serum, the whole body, and critical organs.[5]
1. Mass Dose
Some medical imaging agents can be administered at low mass doses. For example, the mass dose of a single administration of a diagnostic 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 agent is administered at a mass dose that is at the low end of the dose-response curve, dose-related adverse events are less likely to occur.
2. Route of Administration
Some medical imaging agents 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, nonradiolabeled contrast agents pose safety issues similar to therapeutic drugs because of the inherently large amounts needed for administration. Therefore, nonradiolabeled drugs generally should be treated like therapeutic agents for the purpose of conducting clinical safety assessments.
3. Frequency of Use
Many medical imaging agents, including both contrast agents and diagnostic radiopharmaceuticals, are administered infrequently 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. In clinical settings where it is possible that the medical imaging agent will be administered to a single patient repeatedly (e.g., to monitor disease progression), we recommend that repeat-dose studies (of 14 to 28 days’ duration) be performed to assess safety.
Biological medical imaging agents are frequently immunogenic, and the development of antibodies after intermittent, repeated administration can alter the pharmacokinetics, biodistribution, safety, and/or imaging properties of such agents and, potentially, of immunologically related agents. We recommend that studies in which repeat dosing of a biological imaging agent is planned incorporate pharmacokinetic data, human anti-mouse antibody (HAMA), human anti-humanized antibody (HAHA), or human anti-chimeric antibody (HACA) levels as well as whole body biodistribution imaging to assess for alterations in the biodistribution of the imaging agent following repeat dosing. Studies of immunogenicity in animal models are generally of limited value. Therefore, we recommend that human clinical data assessing the repeat use of a biological imaging agent be obtained prior to application for licensure of such an agent.
4. Biological, Physical, and Effective Half-Lives
Diagnostic radiopharmaceuticals often use 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[6] that require an understanding of the kinetics of the distribution and excretion of the radionuclide and its mode of decay. We recommend that biological, physical, and effective half-lives be considered in planning appropriate safety and dosimetry evaluations of diagnostic radiopharmaceuticals.
B. Performance of Nonclinical Safety Assessments
We recommend that the nonclinical development strategy for an agent be based on sound scientific principles, the agent's unique chemistry (including, for example, those of its components, metabolites, and impurities), and the agent’s intended use. Because each product is unique, we encourage sponsors to consult with us before submitting an IND application and during product development. The number and types of nonclinical studies recommended would depend in part on the phase of development, what is known about the agent or its pharmacologic class, its proposed use, and the indicated patient population. If you determine that nonclinical pharmacology or toxicology studies are not needed, we are prepared to grant a waiver under 21 CFR 312.10 if you provide adequate justification.
In the discussion that follows, a distinction is made between drug products and biological products. Existing specific guidance for biological products is referenced but not repeated here (see section III.B.2).
1. Nonclinical Safety Assessments for Nonbiological Drug Productsa. Timing of Nonclinical Studies Submitted to an IND Application
We recommend that nonclinical studies be timed so that they help facilitate the timely conduct of clinical trials (including appropriate safety monitoring based on findings in nonclinical studies) and to reduce the unnecessary use of animals and other resources.[7] The recommended timing of nonclinical studies for medical imaging drugs is summarized in Table 1.
b. Contrast AgentsBecause of the characteristics of contrast drug products (e.g., variable biologic half-life) and the way they are used, we recommend that nonclinical 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. (Exceptions are products with long residence time, e.g., > 90 days.)
· Long-term rodent carcinogenicity studies usually can be omitted.[8]
· Reproductive toxicology studies required under § 312.23(a)(8)(ii)(a) often can be limited to an evaluation of embryonic and fetal toxicities in rats and rabbits and to evaluations of reproductive organs in other short-term toxicity studies.[9] If you determine that such reproductive studies are not needed, we are prepared to grant a waiver under § 312.10 if you provide adequate justification.
We recommend that studies be conducted to address the effects of large mass dose and volume (especially for iodinated contrast materials administered intravenously); osmolality effects; potential transmetalation of complexes of gadolinium, manganese, or iron (generally MRI drugs); potential effects of tissue or cellular accumulation on organ function (particularly if the drug is intended to image a diseased organ system); and the chemical, physiological, and physical effects of ultrasound microbubble drugs (e.g., coalescence, aggregation, margination, and cavitation).
Table 1: Timing of Nonclinical Studies for Nonbiological Products Submitted to an IND
(a) See the guidances S7A Safety Pharmacology Studies for Human Pharmaceutical and S7B Safety Pharmacology Studies for Assessing the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals (note that S7B allows for phase evaluation of the required studies). (b) See the guidance Single Dose Acute Testing for Pharmaceuticals. (c) When repeat-dose toxicity studies have been performed, but single-dose toxicology studies have not, dose selection for initial human studies will likely be based on the results of the no-adverse-effect level (NOAEL) obtained in the repeat-dose study. The likely result will be a mass dose selection for initial human administration that is lower than if the dose selection had been based on the results of acute, single-dose toxicity studies. (d) See radiopharmaceutical discussion in section III.B.1.c of this document.
c. Diagnostic Radiopharmaceuticals (Nonbiological Products)
Because of the characteristics of diagnostic radiopharmaceuticals and the way they are used, we recommend that nonclinical safety evaluations of these drugs be made more efficient by the following modifications:
· 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.[10]
· 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.[11]
We recommend that special safety considerations for diagnostic radiopharmaceuticals include verification of the mass dose of the radiolabeled and unlabeled moiety; assessment of the mass, toxic potency, and receptor interactions for any unlabeled moiety; assessment of potential pharmacologic or physiologic effects due to molecules that bind with receptors or enzymes; and evaluation of all components in the final formulation for toxicity (e.g., excipients, reducing drugs, stabilizers, anti-oxidants, chelators, impurities, and residual solvents). We recommend that the special safety considerations include an analysis of particle size (for products containing particles) and an assessment of instability manifested by aggregation or precipitation. We also recommend that an individual component be tested if specific toxicological concerns are identified or if toxicological data for that component are lacking. However, if toxicological studies are performed on the combined components of a radiopharmaceutical and no significant toxicity is found, toxicological studies of individual components are seldom required.
2. Nonclinical Safety Assessments for Biological Products
Many biological products raise relatively distinct nonclinical issues such as immunogenicity and species specificity. We recommend the following Agency documents be reviewed for guidance on the preclinical evaluation of biological medical imaging agents:
· S6 Preclinical Safety Evaluation of Biotechnology‑Derived Pharmaceuticals
· Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use
Sponsors are encouraged to consult with the appropriate reviewing division for additional information when needed.
IV. CLINICAL SAFETY ASSESSMENTS
Under section 505(d) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355(d)), FDA cannot approve a new drug application (NDA) unless it contains adequate tests demonstrating whether the proposed drug product is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling.[12] All drugs have risks, including risks related to the intrinsic properties of the drug, the administration process, the reactions of the patient, and incorrect diagnostic information. Incorrect diagnostic information includes inaccurate structural, functional, physiological, or biochemical information; false positive or false negative diagnostic determinations; and information leading to inappropriate decisions in diagnostic or therapeutic management. Even if risks are found to be small, all drug development programs must also obtain evidence of drug effectiveness under section 505 of the Act. Although it has been suggested that a demonstration of effectiveness not be required for safer drugs, this statutory requirement cannot be waived. FDA weighs the benefits and risks of each proposed drug product when making its decision about whether to approve a marketing application (e.g., an NDA or BLA).
A. Group 1 and 2 Medical Imaging Agents
The special characteristics of medical imaging agents may allow for a more efficient clinical safety program. This guidance describes two general categories for medical imaging agents: Group 1 and Group 2. The extent of clinical safety monitoring and evaluation that we recommend differs for these two categories. Generally, a less extensive clinical safety evaluation is appropriate for Group 1 agents. Conversely, we recommend that Group 2 agents undergo standard clinical safety evaluations in clinical trials throughout their development. These different groups have been conceived to help drug sponsors identify and differentiate those characteristics that are of greatest interest to the Agency in assessing the potential safety of a medical imaging agent.
FDA anticipates that it can assess which agents are Group 1 agents based on the safety-margin criteria from animal studies and initial human trials completed at the end of Phase 1.
1. Group 1 Medical Imaging Agents
For purposes of this guidance, a Group 1 medical imaging agent generally exhibits the following three characteristics.
· The medical imaging agent meets either the safety-margin considerations or the clinical-use considerations described below (see sections B.1 and B.2, respectively). · The medical imaging agent is not a biological product[13], [14] · The medical imaging agent does not predominantly emit alpha or beta particles Note that under the safety margin criteria (see section IV.B), medical imaging agents that are administered in low mass doses to humans (e.g., diagnostic radiopharmaceuticals) usually are more likely to be considered Group 1 than those administered in higher mass doses.[15] There are important exceptions, including cases where the medical imaging agents are likely to be immunogenic (e.g., biological products) when the pharmacologic response exists at a low mass dose, or when the medical imaging agents cause adverse reactions that are not dose-related (e.g., idiosyncratic drug reactions). We recommend that standard clinical safety evaluations be performed in all clinical investigations of medical imaging agents, but we suggest that, for Group 1 agents, reduced human safety monitoring may be appropriate in subsequent human trials.
· For example, human safety monitoring may be limited to recording adverse events and monitoring only particular organs or tissues of interest for toxicity (such as organs that showed toxicity in the animal studies, or the organs and tissues in which the medical imaging agent localizes, which usually would include the liver and kidneys).
Persons having questions about whether a medical imaging agent is a Group 1 agent are encouraged to contact FDA to discuss. Whether a medical imaging agent should be considered a Group 1 or Group 2 agent may change during the course of a product’s development. For example, even if an agent is initially thought to be Group 1, the subsequent identification of safety concerns could be reason to treat that agent as a Group 2 agent for the remainder of the product’s development.
2. Group 2 Medical Imaging Agents
For purposes of this guidance, Group 2 medical imaging agents are generally medical imaging drugs or biological products that do not fall under the considerations for Group 1 medical imaging agents. All biological products are assumed to be Group 2 agents unless the sponsor demonstrates that its 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 should also be considered Group 2 agents.[16]
For Group 2 medical imaging agents, standard clinical safety evaluations should include serial assessments of patient symptoms, physical signs, clinical laboratory tests (e.g., blood chemistry, hematology, coagulation profiles, urinalyses), other tests (e.g., electrocardiograms as appropriate), and adverse events. We recommend that additional specialized evaluations be performed when appropriate (e.g., immunological evaluations, creatine kinase isoenzymes), or if a particular toxicity is deemed possible based on animal studies or the known chemical or pharmacological properties of the medical imaging agent. Although the extent of clinical monitoring cannot be predetermined, we recommend that it be of sufficient duration to identify possible effects that may lag behind those predicted by pharmacokinetic analyses. If some of these standard clinical safety evaluations are felt to be unnecessary, this should be discussed with the reviewing division. We recommend that sponsors seek FDA comment on the clinical safety monitoring plans in clinical studies before such studies are initiated.
B. Considerations For Groups 1 or 21. Safety-Margin Considerations
Under the safety-margin considerations, medical imaging agents can be considered Group 1 if the results of nonclinical studies and initial human experience are consistent with the conditions outlined below:
a. Results of nonclinical studies
To be considered a Group 1 agent under the safety-margin considerations, we recommend that a medical imaging agent have an adequately documented margin of safety as assessed in the nonclinical studies outlined in the following list.[17]
• We recommend that the no-observed-adverse-effect level (NOAEL)[18] in expanded-acute, single-dose toxicity studies in suitable animal species be at least one hundred times (100x) greater than the maximal mass dose to be used in human studies. We further recommend that such expanded, acute, single-dose toxicity studies be completed before the medical imaging agent is introduced into humans (see section III.B.1).
· We recommend that the NOAEL in safety pharmacology studies in suitable animal species be at least one hundred times (100x) greater than the maximal mass dose to be used in human studies. We further recommend that such safety pharmacology studies be completed before the medical imaging agent is introduced into humans (see section III.B.1).
· We recommend that the NOAEL in short-term, repeat-dose toxicity studies in suitable animal species be at least twenty-five times (25x) greater than the maximal mass dose to be used in human studies.[19] Short-term, repeat-dose toxicity studies are conducted to evaluate the effects of exaggerated dose regimens. Such regimens can reveal effects not detected in studies of small numbers of patients, suggest effects to be monitored in clinical studies, and reveal effects that might occur in sensitive individuals. Short-term, repeat-dose toxicity studies can be performed either before the medical imaging agent is introduced into humans, or concurrently with early human studies, but we recommend that they be completed before phase 2 (see section III.B.1).
To establish these margins of safety, we recommend that the NOAELs be assessed in properly designed and conducted studies and be appropriately adjusted. Appropriately adjusted means that mass dose comparisons between animals and humans should be suitably modified for factors such as body size (e.g., body surface area) and otherwise adjusted for possible pharmacokinetic and toxicokinetic differences between animals and humans (e.g., differences in absorption for products that are administered orally).[20]
We recommend that Group 1 medical imaging agents also undergo other nonclinical toxicological studies as described in section III.B.1, such as genotoxicity, reproductive toxicity, irritancy studies, and drug-drug interaction studies. See section III.B.1 for details and timing sequence.
i. Additional considerations
FDA may still consider a medical imaging agent Group 1 even if its NOAELs are slightly less than the multiples specified above. For example, FDA will also take into consideration, among other things, how close the NOAELs are to the multiples specified above, the amount of safety information known about chemically similar and pharmacologically related medical imaging agents, the nature of observed animal toxicities, and whether adverse events have occurred during initial human experience, including the nature of such adverse events (see section IV.B.1.b).
ii. Formulations used in nonclinical studies
We recommend that the formulation used to establish safety margins in nonclinical studies be identical to the formulation that will be used in clinical trials and that is intended for marketing. We also recommend that any differences in the formulations used in the clinical trials and nonclinical studies be specified so that any effect on the adequacy of the nonclinical studies can be determined. Bridging studies may be helpful when changes in the formulation are apt to change the pharmacokinetics, the pharmacodynamics, or safety characteristics of the drug.[21]
In some cases, it may be infeasible or impractical to administer the intended clinical formulation to animals in multiples of the maximal human mass dose specified above (e.g., the volume of such an animal mass dose may be excessive). We recommend that sponsors discuss their plans with FDA before studies are initiated. In these cases, alternative strategies can be employed, such as dividing the daily mass dose (e.g., into a morning and evening dose), or by using a more concentrated formulation of the medical imaging agent, or the maximal feasible daily mass dose can be administered. b. Results of initial human experience
In addition to those considerations described above for nonclinical studies, FDA also intends to consider the following when evaluating whether a medical imaging agent is a Group 1 agent.
· Whether safety issues were identified during initial human use of the medical imaging agent in appropriately designed studies that include adequate and documented standard clinical safety evaluations. Identification of any adverse events during initial human use that were not predicted from effects observed in animals could be considered significant, regardless of severity. If adverse events occur at any time during human studies, we intend to conduct a risk assessment to determine whether the medical imaging agent should be reconsidered as a Group 2 medical imaging agent. This risk assessment will examine the type, frequency, severity, and potential attribution of the adverse events with respect to what is known about the pharmacology of the drug. For example, the safety profile of a specific drug class may be well known, so that the occurrence of a common, nonserious adverse event, such as headache, would not be of particular concern. However, in a drug class in which microparticles of varying sizes are administered, the occurrence of the same adverse event might be a signal of microcirculatory compromise.
· We recommend that human pharmacokinetic studies of the radiopharmaceutical be performed during phase 1 to collect information about the disposition of the radioactivity in humans. Such data help facilitate adequate comparisons of exposure between humans and the species used in the nonclinical studies and allow a more meaningful assessment of the relevance of the animal safety data (e.g., toxicokinetics).
2. Clinical Use Considerations
Another way to be considered a Group 1 agent is by adequately documenting extensive prior clinical use without development of a safety signal. This means showing that there were no human toxicity or adverse events with clinical mass doses (and activities, if applicable) of the agent, under conditions of adequate safety monitoring, and that the lack of human toxicity was adequately documented. We recommend that the methods used to monitor for adverse events be documented. Literature may be of limited value in establishing the clinical safety of a drug because most published studies focus on efficacy, with little or no description of any safety assessments.
An agent can be identified as Group 1 based on the clinical-use considerations at any time during drug development (e.g., after the conditions specified in this section have all been met). C. Radiation Safety Assessment for All Diagnostic Radiopharmaceuticals1. Ge |