Streamlining first-in-human PET radiopharmaceutical development: FDA's evolving stance on preclinical dosimetry.

The Food and Drug Administration (FDA) Modernization Act (the Modernization Act) of 1997 directed FDA to establish current good manufacturing practice (CGMP) requirements for positron emission tomography (PET) drugs. As directed by the US Congress in the Modernization Act, the costly CGMP regulations which the FDA applies to large pharmaceutical manufacturers are not appropriate for the PET drugs due to the unique properties of these drugs mainly the short half-lives. In consideration of the unique nature of PET drugs and PET drug production, FDA instituted specific CGMP requirements in 21 Code of Federal Regulations (CFR) part 212. Sections 1 and 2 of this book chapter illustrate the significant different aspects and the rationales for such differences between part 212 and parts 210/211 which are the CGMP requirements for non-PET drugs. The PET drug CGMP regulation found in part 212 also provides a more flexible regulatory framework for investigational PET drugs for human use produced under an investigational new drug application (IND) in accordance with part 312 and PET drugs produced with the approval of a Radioactive Drug Research Committee (RDRC) in accordance with part 361. The PET CGMP requirements for these PET drugs can be met either by compliance with part 212 or by producing such drugs in accordance with the 32nd edition of the United States Pharmacopeia (USP) General Chapter , “Radiopharmaceuticals for Positron Emission Tomography – Compounding,” which was published in 2009. In 2012, USP revised and renamed this General Chapter , “Positron Emission Tomography Drugs for Compounding, Investigational, and Research Uses.” FDA is currently considering whether to amend the PET CGMP regulations to incorporate this revised chapter into part 212. Section 4 describes format/content of the revised USP General Chapter which is very much in line with part 212 and offers more flexible requirements than the in 32nd USP.

The recent progress in our understanding of the molecular-genetic mechanisms active in many diseases and the application of new biologically based approaches in therapy are exciting new developments that have emerged following mapping of the human genome. Novel “molecular therapies” have been

Positron emission tomography (PET) has been used for almost 30 years to quantify normal physiology and metabolism, to characterize disease, and to evaluate the changes resulting from disease processes. The data that have been developed from these research applications have led to the clinical applications. Clinical PET is one of the many uses of PET, including clinical care, and it is reimbursed by insurance companies. Clinical PET became a reality only after widespread reimbursement became available for the procedure. Rapid growth in the utilization of PET is directly related to changes in radiopharmaceutical regulation and reimbursement. In the Food and Drug Administration (FDA) Modernization and Accountability Act passed by Congress in 1997, it was stated that PET radiopharmaceuticals have the equivalence of FDA approval until a new process for regulating PET radiopharmaceuticals is developed. In 1998, the Health Care Financing Administration (HCFA) began covering fluorodeoxyglucose (FDG)-PET for the evaluation of solitary pulmonary nodules (G code 0125), initial staging of lung cancer (G0126), detection of recurrent colorectal cancer with rising carcinoembryonic antigens (G0163), staging of lymphoma (G0164), and detection of recurrent malignant melanoma (G0165). The HCFAapproved indications were paid using G codes, and hospital outpatients have been reimbursed using the Ambulatory Payment Classification (APC). The PET imaging devices, both dedicated and hybrid systems, have been also covered.1 The growing recognition of the cost-effectiveness of FDG-PET in cancer management has made oncology the focus for most clinical PET studies.2

FDA's role in anesthetic drug development.

Chapter 17: PET Radiopharmaceutical Manufacturing and Distribution

“Black box” 101: How the Food and Drug Administration evaluates, communicates, and manages drug benefit/risk

Successful Investigational New Drug Preparation without Reinventing the Wheel

Prostate cancer is characterized by evolution from a clinically localized hormone-naive state in the prostate gland to an eventually castration-resistant metastatic state. Clinical imaging tools employed in the diagnosis of prostate cancer include transrectal ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and bone scans. Unfortunately, the likelihood of disease detection with these modalities is low. The structural imaging techniques such as CT and MRI provide details about the anatomy and anatomical relations such as size, local invasions, tumor borders, and anatomical distortions. In contrast, molecular imaging based on single-photon emission computed tomography (SPECT) and positron emission tomography (PET) radiopharmaceuticals is a type of medical imaging that provides detailed pictures of what is happening inside the body noninvasively at the molecular and cellular level and offers unique insights into the human body that enable physicians to personalize patient care. The molecular imaging radiopharmaceuticals target specifically biologically relevant molecules such as enzymes involved in the metabolism of glucose and fatty acids, receptors such as androgen receptors (AR), and antigens such as prostate-specific membrane antigen (PSMA). The current Food and Drug Administration (FDA)-approved molecular imaging radiopharmaceuticals include 99mTc-labeled bone imaging agents and 111In-labeled anti-PSMA antibody (ProstaScint™) for SPECT and [18F]fluorodeoxyglucose, [18F]sodium fluoride (NaF), and [11C]choline (CH) for PET. Emerging agents under clinical development include radiolabeled analogs of lipid, amino acid, and nucleoside metabolism, as well as other small molecules more specifically targeting prostate cancer biomarkers including AR and PSMA. In the last 5 years, several small-molecule PSMA inhibitors labeled with 123I or 99mTc (for SPECT) and 18F or 68Ga (for PET) have been evaluated in phase I and II clinical studies and show significant diagnostic potential for molecular imaging studies of prostate cancer. As the management of prostate cancer becomes more personalized and new treatments become available, there is increasing clinical demand for molecular imaging for prostate cancer diagnosis. In this chapter, we have highlighted a great number and variety of emerging molecular imaging agents for prostate cancer diagnosis.

Positron emission tomography (PET) has been used for almost 37 years to quantify normal physiology and metabolism, to characterize disease, and to evaluate the changes resulting from disease processes. The data that have been developed from these research applications have led to the clinical applications. Clinical PET is one of the many uses of PET, including clinical care, and it is reimbursed by insurance companies. Clinical PET became a reality only after widespread reimbursement became available for the procedure. Rapid growth in the utilization of PET is directly related to changes in radiopharmaceutical regulation and reimbursement. In the Food and Drug Administration (FDA) Modernization and Accountability Act passed by Congress in 1997, it was stated that PET radiopharmaceuticals have the equivalence of FDA approval until a new process for regulating PET radiopharmaceuticals is developed. In 1998, the Health Care Financing Administration (HCFA) began covering fluorodeoxyglucose (FDG) PET for the evaluation of solitary pulmonary nodules, initial staging of lung cancer, detection of recurrent colorectal cancer with rising carcinoembryonic antigens, staging of lymphoma, and detection of recurrent malignant melanoma. The HCFA-approved indications were paid using G codes, and hospital outpatients have been reimbursed using the Ambulatory Payment Classification. The PET imaging devices, both dedicated and hybrid systems, have also been covered (Coleman et al. J Nucl Med 42:11–12N, 1999). The growing recognition of the cost effectiveness of FDG PET in cancer management has made oncology the focus for most clinical PET studies (Coleman J Nucl Med 40:814–20, 1999).

Electronic Generators for the Production of Positron-Emitter Labeled Radiopharmaceuticals: Where Would PET Be Without Them?

The future of drug safety: What the IOM report may mean to the emergency department

British chef and food activist Jamie Oliver ignited a firestorm in January 2011 when he mentioned on the Late Show with David Letterman that castoreum, a substance used to augment some strawberry and vanilla flavorings, comes from what he described as “rendered beaver anal gland.”1 The next year, vegans were outraged to learn that Starbucks used cochineal extract, a color additive derived from insect shells, to dye their strawberry Frappuccino® drinks2 (eventually, the company decided to transition to lycopene, a pigment found in tomatoes3). Although substances like castoreum and cochineal extract may be long on the “yuck factor,”4 research has shown them to be perfectly safe for most people; strident opposition arose not from safety issues but from the ingredients’ origins. But these examples demonstrate that the public often lacks significant knowledge about the ingredients in foods and where they come from. This is not a new development; the public relationship to food additives has a long history of trust lost, regained, and in some cases lost again. The Federal Food, Drug, and Cosmetic (FD&C) Act of 19385 was passed shortly after the deaths of 100 people who took an untested new form of a popular drug, which contained what turned out to be a deadly additive.6 The new law was consumer oriented and intended to ensure that people knew what was in the products they bought, and that those products were safe. The law has been amended over the years in attempts to streamline and bring order to the sprawling task of assessing and categorizing the thousands of substances used in foods, drugs, and cosmetics. One result of this streamlining is that under current U.S. law, companies can add certain types of ingredients to foods without premarket approval from the thin-stretched Food and Drug Administration (FDA). In other words, there are substances in the food supply that are unknown to the FDA. In 2010 the Government Accountability Office (GAO) concluded that a “growing number of substances … may effectively be excluded from federal oversight.”7 Is this a problem? The answer depends on whom you ask.

A recent Food and Drug Administration (FDA) proposal aims to speed the evaluation process for new high-risk medical devices that are intended to address unmet medical needs,1 much like existing expedited approval processes, such as the humanitarian device exemption rule for devices intended to treat rare diseases. Such programs are strongly supported by the medical device industry and some patient advocacy groups, which have criticized the FDA for being too stringent in its evidentiary requirements for investigational devices, leading to delays in the approval of potentially helpful products.2–4 For example, in 2011, the FDA approved a transcatheter aortic valve replacement system that demonstrated significant improvements over conventional treatment options for selected patients with severe aortic stenosis.5,6 However, the United States was the 43rd country to approve the device, roughly 4 years after the European Union.7 Yet expedited approval for high-risk medical devices raises the possibility that these devices will not be as effective as predicted in their limited premarket testing or that they could cause unanticipated harms after approval.8 Of course, well-studied devices may present unexpected safety concerns years after approval,9,10 and even the most rigorous conventional premarket approval process will result in some devices later found to be unsafe or ineffective.11–13 Safety of approved medical devices and the proper scope of premarket testing remain contentious issues after recalls of several widely used devices, including popular models of implantable cardioverter defibrillator leads14,15 and metal-on-metal hip implants.16 Inherent limitations in premarket testing, along with the prospect of lowered evidentiary standards for expedited device reviews, place greater pressures on postapproval monitoring of devices to follow clinical performance and to identify emerging public health problems. Medical device manufacturers routinely perform this sort of vigilance, …

PET radiopharmaceuticals: state-of-the-art and future prospects

Safety concerns at the FDA