How Should the FDA Review Diagnostic Radiopharmaceuticals?

The purpose of this article is to reconsider the manner in which the U.S. Food and Drug Administration (FDA) reviews diagnostic radiopharmaceuticals. Mass characteristics of several common nonradioactive drugs and several diagnostic radiopharmaceuticals are considered. A history of the regulation of radiopharmaceuticals is presented. The Society of Nuclear Medicine and Molecular Imaging and the American College of Nuclear Medicine should choose the membership of a radiopharmaceutical advisory committee, and the FDA should contract with them to do so. Members of the radiopharmaceutical advisory committee should decide on the data to be presented by the manufacturer or the compounder and review those data, and the FDA should honor their decision. In this way, requirements would be radiopharmaceutical-specific, and much information of questionable usefulness would be foregone.

Destroying the Linear No-threshold Basis for Radiation Regulation: A Commentary.

This article suggests five classes of effort that scientists can undertake to destroy the linear no-threshold hypothesis as the basis of radiation regulation in the United States. These are (1) pressure on regulators such as the Nuclear Regulatory Commission, (2) presidential messages, (3) Congressional pressure, (4) educate physicians about low-dose radiation, and (5) work with journalists and media people.

Time to Reject the Linear-No Threshold Hypothesis and Accept Thresholds and Hormesis: A Petition to the U.S. Nuclear Regulatory Commission.

On February 9, 2015, I submitted a petition to the U.S. Nuclear Regulatory Commission (NRC) to reject the linear-no threshold (LNT) hypothesis and ALARA as the bases for radiation safety regulation in the United States, using instead threshold and hormesis evidence. In this article, I will briefly review the history of LNT and its use by regulators, the lack of evidence supporting LNT, and the large body of evidence supporting thresholds and hormesis. Physician acceptance of cancer risk from low dose radiation based upon federal regulatory claims is unfortunate and needs to be reevaluated. This is dangerous to patients and impedes good medical care. A link to my petition is available: http://radiationeffects.org/wp-content/uploads/2015/03/Hormesis-Petition-to-NRC-02-09-15.pdf, and support by individual physicians once the public comment period begins would be extremely important.

Licensee over-reliance on conservatisms in NRC guidance regarding the release of patients treated with 131I.

Medical licensees are required to comply with U.S. Nuclear Regulatory Commission (NRC) regulations pertaining to the release of patients administered radioactive material. However, use of the associated NRC guidance expressed in NUREG-1556, Volume 9, is completely optional and has been shown to be overly conservative. Rigid adherence to the guidance recommendations has placed an undue burden on nuclear medicine therapy patients and their families, as well as licensees responsible for ensuring compliance with NRC requirements. More realistic guidance has been published by other responsible professional societies and will be presented in this work. These more realistic calculations allow for higher releasable activity levels than the widely adopted NUREG levels, particularly for thyroid cancer patients. The guidance-suggested releasable activity limit is similar to our calculational result for hyperthyroid patients, 2.1 GBq (57 mCi) compared to 2.3 GBq (62 mCi), but is significantly lower for thyroid cancer patients, 6.6 GBq (179 mCi) vs. 16.9 GBq (457 mCi) using the regulatory definition of the total effective dose equivalent (TEDE). Higher limits are both possible and reasonable, if the permissible extra-regulatory definition of the TEDE is used in which the effective dose equivalent (EDE), rather than the deep-dose equivalent (DDE), is determined. We maintain that professionals evaluating compliance with the NRC requirements for patient release, pursuant to 10 CFR 35.75, should use the procedures presented here and not rely automatically on the NUREG.

A rational regulatory approach for positron emission tomography imaging probes: from "first in man" to NDA approval and reimbursement.

We propose a new regulatory approach for positron emission tomography (PET) molecular imaging probes, essential tools in today's medicine. Even though the focus of this paper is on positron-emitting labeled probes, it is also justified to extend this proposed regulatory approach to other diagnostic nuclear medicine radiopharmaceuticals. Key aspects of this proposal include: (1) PET molecular imaging probes would be placed in a "no significant risk" category, similar to that category for devices in current Food and Drug Administration (FDA) regulations, based on overwhelming scientific evidence that demonstrates their faultless safety profile; (2) the FDA-sanctioned Radioactive Drug Research Committee (RDRC) will oversee all diagnostic research with these probes. The newly defined RDRC should approve "first in man" use; supervise a broader spectrum of diagnostic research protocols, including those looking to demonstrate initial efficacy, as well as multicenter clinical trials and the use of molecular imaging probes as a screening tool in drug discovery. The current investigational new drug (IND) mechanism is thus eliminated for these diagnostic probes; (3) when a molecular imaging probe has demonstrated diagnostic efficacy, FDA approval (i.e., NDA) will be sought. The review will be done by a newly constituted Radioactive Drug Advisory Committee (RDAC) composed of experts chosen by the professional societies, who would provide a binding assessment of the adequacy of the safety and efficacy data. When the RDAC recommends its diagnostic use on scientific and medical grounds, the molecular imaging probe becomes FDA approved. After a molecular imaging probe is approved for a diagnostic indication, the existing mechanism to seek reimbursement will be utilized; and (4) the FDA would retain its direct oversight function for traditional manufacturers engaged in commercial distribution of the approved diagnostic molecular imaging probes (i.e., under NDA) to monitor compliance with existing US Pharmacopeia (USP) requirements. With abbreviated and more appropriate regulations, new PET molecular imaging probes for diagnostic use would be then rapidly incorporated into the mainstream diagnostic medicine. Equally importantly, this approach would facilitate the use of molecular imaging in drug discovery and development, which would substantially reduce the costs and time required to bring new therapeutic drugs to market.

Calculating the absorbed dose from radioactive patients: the line-source versus point-source model.

UNLABELLED: In calculations of absorbed doses from radioactive patients, the activity distribution in such patients is generally assumed to be an unattenuated point source and the dose to exposed individuals at a given distance is therefore calculated using the inverse square law. In many nuclear medicine patients, the activity distribution is widely dispersed and does not simulate a point source. In these cases, a line-source model is proposed to more accurately reflect this extended activity distribution. METHODS: Calculations of dose rate per unit activity were performed for a point source and for line sources of lengths of 20, 50, 70, 100, and 174 cm, and the ratios of line-source values to point-source values were calculated. In addition, radionuclide-independent conversion factors, to convert exposure rate constants to dose rates per unit activity, for these line-source lengths at various distances were determined. RESULTS: The calculated values, substantiated by published data, indicate that the inverse square law approximation is not valid for a line source until a certain distance is reached, dependent on the length of the line source. For the 20-, 50-, 70-, 100-, and 174-cm line sources, the dose rate values estimated by the inverse square law approximation are within approximately 10% of the values estimated using the line-source approach at distances of 20, 45, 60, 85, and 145 cm, respectively. At closer distances, use of the point-source model for a patient with an extended activity distribution will overestimate the radiation absorbed dose to exposed individuals, sometimes by a very significant amount. CONCLUSION: The line-source model is a more realistic and practical approach than the traditional point-source model for determining the dose to individuals exposed to radioactive patients with widespread activity distributions.

Lack of effect of a bisphosphonate (pamidronate disodium) infusion on subsequent skeletal uptake of Sm-153 EDTMP.

Patients who are candidates for samarium-153 ethylenediaminetetramethylenephosphonic acid (Sm-153 EDTMP) therapy often receive monthly infusions of pamidronate disodium or other bisphosphonates. Because both drugs are related compounds that concentrate in bone, it was advisable to determine whether previous bisphosphonate administration has blocked subsequent uptake of Sm-153 EDTMP. The authors compared skeletal uptake of Sm-153 EDTMP before and 1 to 4 days after pamidronate infusion in three patients with breast cancer metastatic to bone. In two of the patients, they continued to compare Sm-153 EDTMP uptake at approximately 1, 2, 3, and 4 weeks after pamidronate infusion. There was no difference in skeletal uptake of Sm-153 EDTMP before or at any time after pamidronate infusion. Pamidronate infusion did not interfere with skeletal uptake of Sm-153 EDTMP.

Administration guidelines for radioimmunotherapy of non-Hodgkin's lymphoma with (90)Y-labeled anti-CD20 monoclonal antibody.

90Y-ibritumomab tiuxetan is a novel radioimmunotherapeutic agent recently approved for the treatment of relapsed or refractory low-grade, follicular, or CD20+ transformed non-Hodgkin's lymphoma (NHL). (90)Y-ibritumomab tiuxetan consists of a murine monoclonal antibody covalently attached to a metal chelator, which stably chelates (111)In for imaging and (90)Y for therapy. Both health care workers and patients receiving this therapy need to become familiar with how it differs from conventional chemotherapy and what, if any, safety precautions are necessary. Because (90)Y is a pure beta-emitter, the requisite safety precautions are not overly burdensome for health care workers or for patients and their families. (90)Y-ibritumomab tiuxetan is dosed on the basis of the patient's body weight and baseline platelet count; dosimetry is not required for determining the therapeutic dose in patients meeting eligibility criteria similar to those used in clinical trials, such as <25% lymphomatous involvement of the bone marrow. (111)In- and (90)Y-ibritumomab tiuxetan are labeled at commercial radiopharmacies and delivered for on-site dose preparation and administration. Plastic and acrylic materials are appropriate for shielding during dose preparation and administration; primary lead shielding should be avoided because of the potential exposure risk from bremsstrahlung. Because there are no penetrating gamma-emissions associated with the therapy, (90)Y-ibritumomab tiuxetan is routinely administered on an outpatient basis. Furthermore, the risk of radiation exposure to patients' family members has been shown to be in the range of background radiation, even without restrictions on contact. There is therefore no need to determine activity limits or dose rate limits before patients who have been treated with (90)Y radioimmunotherapy are released, as is necessary with patients who have been treated with radiopharmaceuticals that contain (131)I. Standard universal precautions for handling body fluids are recommended for health care workers and patients and their family members after (90)Y-ibritumomab tiuxetan administration. In summary, (90)Y-ibritumomab tiuxetan introduces (90)Y into clinical practice and expands the role nuclear medicine plays in the care of patients with cancer. Understanding the unique properties of this novel radioimmunoconjugate will facilitate its safe and effective use.