Se Selenium

Nuclear medicine is one of the areas of medicine that is particularly dependent on basic science. Chemistry, radiochemistry and physics, as well as physiology and biochemistry, are essential ingredients to understand and generate the images that we review. Regardless of this strong basic science component, when we begin to interpret the meaning of the images we see, nuclear medicine becomes as much a part of the “art of medicine” as any other specialty. A very significant component of medical practice is based on clinical experience. Decisions about diagnosis, treatment, and interpretation of images are strongly influenced by the “experience” of the practitioner and his or her intuitive sense of the meaning of the observation and the patient's complaint. This classic “practice of medicine” is no longer acceptable in the 21st century. There is an increasing trend towards “evidence-based” medicine. Third parties that review payment for services rendered and, in the case of nuclear medicine, that approve or disapprove procedures for routine clinical use, are increasingly demanding more strict measures of accuracy, sensitivity and specificity. This journal was one of the first to recognize the importance of this requirement. Acting on the advice and suggestions of Dennis Patton (1930-2007) in 1978 we published an issue devoted to “Decision Making in Clinical Nuclear Medicine” (Dennis D. Patton, MD, Guest Editor, October 1978, pages 271-365). This was one of the earliest publications in clinical medicine devoted to what has now become a routine requirement for the analysis of studies that are performed to shape medical practice. Dennis put together a comprehensive and highly informative seminar that even today has great impact. He wrote an incisive editorial for that issue and the lead article which was entitled “Introduction to Clinical Decision Making.” The editors believe that this is such an important seminal article in this field that we have reprinted his original contribution in this issue where its relevance remains. In 1993 we revisited this subject from a somewhat different point of view in an issue entitled “Socioeconomic Issues in Nuclear Medicine.” Dennis Patton once again provided a seminal contribution on cost-effectiveness in nuclear medicine. In that contribution he made the statement “much work remains to be done in forming a coherent consistent procedure for assessing cost-effectiveness in nuclear medicine.” Here we are 17 years later and we have made some progress, but much work remains to be done.

In the last few years there has been a remarkable increase in the amount of clinical data in the average hospital chart, and more and more problem-solving algorithms have been developed. We need better “thinking tools” to help us handle the flow of information. The term “clinical decision making” is used to describe a systematic way to handle data and algorithms to decide on a best course of action. This introductory article discusses some of the problems in establishing a decision criterion, both for a population and for an individual patient. Comparing the probabilities and utilities of various diagnostic outcomes (true positive, false positive, etc.) leads to a diagnostic strategy. The article also discusses conditional probability. Bayes' theorem, and likelihood ratios.

The Clinical Trials Network of the Society of Nuclear Medicine was formed to provide quality assurance of both imaging and radiopharmaceutical manufacturing in clinical trials. The intention is to register and qualify a large number (>200) of sites, both in the United States and internationally, to be able to do the positron emission tomography imaging part of clinical trials. Initially, the types of trials to be supported include evaluation of novel radiopharmaceuticals and trials that use approved or experimental radiopharmaceuticals for early assessment of tumor response to novel chemotherapy agents. The Clinical Trials Network is organized into 7 committees that provide overall oversight and strategic guidance, database management, site qualification and monitoring, scanner validation, clinical site orientation, technologist education, trial design, and a manufacturer's registry. At the end of the first year, more than 200 potential clinical trial sites and more than 125 manufacturing sites have expressed interest in participating. The qualification process is well underway. Funding is being provided by 3 large pharmaceutical companies. An investigational new drug application has been obtained for F-18 fluorothymidine that is held by Society of Nuclear Medicine to allow simplification of data management during multisite trials with F-18 fluorothymidine. A second investigational new drug application is in preparation for F-18 fluoromisonidazole. A supply of oncology chest phantoms has been manufactured and have been shipped to numerous sites for scanner validation. Educational materials are being developed for the physicians, technologists, and research coordinators at the sites. This is an important initiative that is likely to help significantly expand the role of molecular imaging and will help bring the right treatment to the right patient at the right time.

Clinical trial design for nuclear medicine diagnostic imaging radiopharmaceuticals must include a design for preclinical safety studies. These studies should establish that the investigational product (IP) does not have a toxic effect. As a further requirement, radiopharmaceutical clinical trials include a human study (phase 1) that provides biodistribution, pharmacokinetics, and radiation dosimetry information. These studies demonstrate to the Food and Drug Administration that the IP either meets or exceeds the toxicology and radiation exposure safety limits. Satisfying this requirement can result in the Food and Drug Administration approving the performance of late-phase (phase 2/3) clinical trials that are designed to validate the clinical efficacy of the diagnostic imaging agent in patients who have a confirmed diagnosis for the intended application. Emphasis is placed on the most typical trial design for diagnostic imaging agents that use a comparator to demonstrate that the new IP is similar in efficacy to an established standard comparator. Such trials are called equivalence, or noninferiority, trials that attempt to show that the new IP is not less effective than the comparator by more than a statistically defined amount. Importantly, the trial design must not inappropriately favor one diagnostic imaging agent over the other. Bias is avoided by the use of a core laboratory with expert physicians who are not involved in the trial for interpreting and objectively scoring the image sets obtained at the clinical trial sites. Clinical trial design must also follow Good Clinical Practice (GCP) guidelines. GCP stipulates the clinical trial process, including protocol and Case Report Form design, analyses planning, as well as analyzing and preparing interim and final clinical trial/study reports.

The incorporation of imaging biomarkers and clinical trials is now common. Because of the multiple technical, clinical, and regulatory demands to ensure high-quality quantitative information, the core laboratory serves as a critical intermediary between the study sponsor and the site. It provides unique expertise not found in typical clinical research organizations. This expertise goes far beyond the passive receipt of images for conductance of central reads of data and includes the proactive and early involvement in the selection of sites for imaging, the qualification and assistance for managing the local site logistics, on-the-fly and active quality control of imaging data in close working relationship with sites, and preparation for and conductance of central image reads or quantification in a manner which bears up to regulatory scrutiny.

Clinical investigations of radiopharmaceuticals are undertaken to advance promising compounds toward approval by the Food and Drug Administration (FDA) as “legend drugs.” This FDA approval requires that the safety and efficacy of the investigational drug (ID) be demonstrated through clinical trials. The investigational radiopharmaceutical drug service (IRDS) is a pharmacy service that plays a critical role in the acquisition, preparation, accountability, and distribution of radiopharmaceuticals used in clinical research. Due to their radioactive and other unique properties, and their potential role as biomarkers or tools in clinical trials of other therapeutic drugs, radiopharmaceutical drugs must be managed by a qualified IRDS rather than by a typical pharmacy-based investigational drug service (IDS). The IRDS is responsible for establishing study-specific procedures for appropriate radiopharmaceutical drug accountability, billing, procurement, storage, preparation, dispensing and destruction of investigational drugs within the hospital.All drugs, and particularly parenteral drug products, must be safe for administration to human subjects enrolled in clinical trials regardless of their FDA regulatory status as approved or investigational new drug products. The United States Pharmacopeia (USP) sterile compounding requirements provides enforceable minimum practice and quality standards for compounded sterile preparations of drug products based on current scientific information and best sterile compounding practices. Consequently, they apply equally to facilities dedicated to IDS and IRDS operations. The FDA also regulates drug manufacturing through current Good Manufacturing Practices (cGMP). This rule (21CFR Part 212) establishes cGMP regulations specific to positron emission tomography radiopharmaceuticals, separate from the regular drug cGMP rule (Parts 210 and 211).Compliance with regulatory, statutory, and sponsor requirements is a major consideration in the operation of a radiopharmacy for clinical trials. Sponsors conduct audits as part of the quality assurance of clinical trials. Audits of clinical trial sites by the sponsor, sponsor's clinical research organization, institutional review board, or FDA always include a detailed review of drug accountability records. Audits for radiopharmaceutical drug products typically begin by confirming the clinical site is appropriately licensed and authorized to receive, possess, store, handle, prepare and administer radiopharmaceuticals. All procedures for radiopharmaceutical drug accountability must comply with applicable federal regulations and the specific requirements specified by the study sponsor.

The randomized clinical trial is widely viewed to be the gold standard for evaluation of treatments, diagnostic procedures, or disease screening. The proper design and analysis of a clinical trial requires careful consideration of the study objectives (eg, whether to demonstrate treatment superiority or noninferiority) and the nature of the primary end point. Different statistical methods apply when the end point variable is discrete (counts), continuous (measurements), or time to event (survival analysis). Other complicating factors include patient noncompliance, loss to follow-up, missing data, and multiple comparisons when more than 2 treatments are evaluated in the same study. This article provides an overview of the basic statistical approaches for analyzing clinical trials with binary, continuous or time-to-event outcomes as well as methods for handling protocol deviations due to noncompliance and early drop-out. Issues surrounding the determination of sample size and power of clinical trials are also discussed.

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.

Several ethical transgressions involving human subjects in scientific research during the last century have led to guidelines for acceptable research conduct and oversight. Thoughtful examination of these events yielded ethical documents whose principles eventually became codified into federal regulations governing research. These regulations specify the composition and function of the institutional review board (IRB), as well as the criteria by which the IRB judges the acceptability of proposed research. Continuous advances in medicine and technology generate the need to test new and potentially viable interventions for safety and efficacy. These advances in medical science rely heavily on the altruism and sometimes heroism of individuals who put their own well being at risk for the benefit of others by participating in clinical research experiments. It is therefore necessary for researchers to understand the function of the IRB and ethics review committees from which approval is required before research in human subjects may begin. Understanding the function of the IRB requires an appreciation for the rules by which it is governed, as well as the history and circumstances that influenced the creation of those rules. Researchers who appreciate the IRB's purpose will be better equipped to navigate the labyrinth of research guidelines and regulations.

It is requisite in all areas of diagnostic imaging that interpreting physicians are fountain trained to recognize not solely the great altering that exists in the “normal” study, but also the divers deviations that may crop up from a variation of complex factors. This may be more pertaining for radionuclide imaging than other areas of diagnostic imaging. The radiopharmaceuticals that we administer go through a actually baroque function consanguineous to their preparation. Tranquil slight deviations can spadework to radiochemical or radiopharmaceutical impurities. Labeling problems and variants associated with provision technique can significantly modify the division of project on a radionuclide form. Invalid preparation, such as fasting, blood glucose levels, etc, undertake an pompous rÂle as well <<>>