Radiopharmaceuticals for Drug Development: United States Regulatory Perspective

Abstract

Imaging with radiopharmaceuticals is playing an increasingly important role in the development of new drugs. At nearly every step of the process imaging may be used to assess the status of the candidate drugs and assist in determining the lead molecules for further evaluation. Incorporating imaging studies into the paradigm may ameliorate the temporal and economic cost of drug development. Since 1975 radiopharmaceuticals have been regulated as drugs and all human studies must be carried out under an investigational new drug (IND) or radioactive drug research committee (RDRC) protocol. The FDA released the exploratory IND guidance in 2006 to highlight the flexibility in the IND process while trying to stimulate new drug entry into the approval pipeline. The exploratory IND also provides a lower threshold for radiopharmaceutical and candidate drug first in human studies, using the microdosing concept, that may not be conducted under an RDRC protocol. The RDRC mechanism permits the basic research studies with limited dose and numbers of subjects. The RDRC regulations are 30 years old and the full IND process remains burdensome for radiopharmaceutical development. Therefore, it is essential that the regulatory framework permit the approval of radiopharmaceuticals for use in humans that is commensurate with the safety and applications of the probes. Beyond diagnosing and staging disease, monitoring progression or therapeutic intervention, imaging is playing an increasingly important role in the drug discovery and development process. Nuclear imaging, positron emission tomography (PET) and single photon emission computed tomography (SPECT), with radiolabeled molecular entities, radiopharmaceuticals, permits the visualization of the distribution of potential drugs as well as interrogating their effect on disease, organ systems and the whole body. Imaging probes may be applied in two ways to drug development, i) to define the pharmacokinetic (PK) properties of labeled drug candidates or ii) to assess the pharmacodynamic (PD) properties of new drugs. Molecular imaging's role in drug discovery and development has grown significantly over the last decade and it will continue to have a major impact on the assessment and profiling of new drugs for the foreseeable future. Since 1975 radioactive labeled entities, small molecules and biologics, have been considered by the United States Food and Drug Administration (FDA) to be drugs and are regulated as such. In spite of the fact that imaging probes, by their very nature, are tracers with minimal mass and no expected pharmacological or toxicological properties, they must undergo extensive safety evaluation prior to approval by the FDA. All human studies involving radioactively labeled molecules, unless exempt, must be performed under FDA guidelines using either an investigational new drug (IND) a or Radioactive Drug Research Committee (RDRC) b approval mechanism. This article describes the United States regulatory pathways that are involved to permit the use of new and existing radiopharmaceuticals in the drug discovery and development process.