Food and Drug Administration requirements for testing and approval of new radiopharmaceuticals.

In March 2004, the Food and Drug Administration (FDA) published a report entitled Challenge and Opportunity on the Critical Path to New Medical Products in which it explained the critical path to medical product development and called for a nationwide effort to modernize the critical-path sciences with the aim of moving medical product development and patient care into the 21st century. The report identified medical imaging and imaging biomarkers as potential clinical development tools to facilitate medical product development and to help minimize drug attritions and development timelines. Also, in recent years, basic research on receptor-based imaging has led to an increase in the new investigational radiopharmaceuticals, many of which are in basic research stages in academic institutions. It is therefore an opportune time to review the FDA requirements for testing and approval of new radiopharmaceuticals to further the cause of development and approval of newer medical imaging and therapeutic agents. Although the radiopharmaceutical-development process aligns well with the drug-development process for conventional pharmaceuticals, it has its own challenges and unique considerations. For example, unique issues surrounding short-lived positron emission tomography drugs have necessitated revisions and refinements to the existing regulations. The FDA Modernization Act mandate has finally resulted in the publication of new cGMPs (current good manufacturing practice) for positron emission tomography drugs. Often, the radiopharmaceutical community is not well-informed about the regulatory pathways and scientific basis for the regulations they are subjected to. Questions, such as (1) "Do I need an investigational new drug (IND) or can I do my investigation under an RDRC (radioactive drugs research committee) oversight?" (2) "What type of information on radiopharmaceutical product quality is needed for an IND?" (3) "What level of cGMPs I am expected to operate under?" (4) "Do I need a traditional IND or can I perform studies under an exploratory IND?" (5) "What are the IND-enabling pharmacology and toxicology studies?" (6) "Is my practice consistent with pharmacy compounding or do I need to file an application with the FDA?", for example, are a source of confusion to the radiopharmaceutical community. This review provides an overview of FDA's drug development and approval process with special emphasis on radiopharmaceuticals and attempts to clarify many regulatory issues and questions by providing appropriate discussion and FDA references.

Vorinostat for treatment of cutaneous manifestations of advanced primary cutaneous T-cell lymphoma.

PURPOSE: To discuss vorinostat approval for treatment of cutaneous manifestations of advanced cutaneous T-cell lymphoma (CTCL). EXPERIMENTAL DESIGN: Data from 1 single-arm, open-label, multicenter pivotal trial and 11 other trials submitted to support the new drug application for vorinostat in the treatment of advanced primary CTCL were reviewed. The pivotal trial assessed responses by changes in overall skin disease score using a severity-weighted assessment tool (SWAT). Vorinostat could be considered active in CTCL if observed response rate was at least 20% and the lower bound of the corresponding 95% confidence interval (95% CI) excluded 5%. Patients reported pruritus relief using a questionnaire and a visual analogue scale. RESULTS: The pivotal trial enrolled 74 patients with stage IB or higher CTCL. Median number of prior treatments was 3, and 61 patients (82%) had stage IIB or higher disease. The objective response rate in the skin disease assessed by change in the overall SWAT score from the baseline was 30% (95% CI, 18.5 to 42.6) in patients with stage IIB or higher disease. Median response duration (end of response defined by 50% increase in SWAT score from the nadir) was 168 days. Median time to tumor progression was 148 days for overall population and 169 days for patients with stage IIB or higher disease. Assessment of pruritus relief was considered unreliable. CONCLUSIONS: Vorinostat showed activity in CTCL, and skin responses were a clinical benefit. Vorinostat was approved for treatment of cutaneous manifestations of CTCL. A nonblinded, single-arm trial did not allow a reliable assessment of pruritus relief.

Synthesis and biologic evaluation of a radioiodinated quinazolinone derivative for enzyme-mediated insolubilization therapy.

We have developed a new strategy that aims to concentrate therapeutic radionuclides within solid tumors. This approach, which we have named EMIT (enzyme-mediated insolubilization therapy), is a method for enzyme-dependent, site-specific, in vivo precipitation of a radioactive molecule (from a water-soluble precursor) within the extracellular space of solid tumors. The prodrug, ammonium 2-(2'-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone, labeled with iodine-125 ((125)IPD) and its authentic compound labeled with iodine-127 (IPD) have been synthesized, purified, and characterized. The alkaline phosphatase (ALP)-mediated conversion of these water-soluble nonfluorescent prodrugs to the water-insoluble fluorescent species, iodine-125-labeled 2-(2'-hydroxyphenyl)-6-iodo-4-(3H)-quinazolinone ((125)ID) and its iodine-127-labeled derivative (ID), has been demonstrated in vitro. Biodistribution studies in mice indicate that both (125)IPD and (125)ID are minimally retained by most tissues and organs. In addition, following its intravenous injection in mice, (125)IPD is localized in ALP-rich regions and converted to (125)ID, which remains indefinitely within the tissues where it is produced. We believe that EMIT is a strategy that will lead to the active and specific concentration and entrapment of therapeutic radionuclides within solid tumors, the consequent protracted irradiation of tumor cells within the range of the emitted particles, and the effective therapy of solid tumors.