Approval Status and Regulatory Actions for Radiopharmaceuticals in the United States and Japan

Abstract

The aim of this study was to identify the differences between Japan and the United States in the approval status and regulatory actions for radiopharmaceuticals. The package inserts of radiopharmaceuticals that have been approved in the United States and Japan were used to investigate the status of approval in each country, examining the similarities and differences thereof and taking the regulatory systems of the 2 countries into account. Results revealed that since 1995, fewer products have been approved in Japan than in the United States: 16 radiopharmaceuticals have been approved in the United States, compared to only 7 in Japan. Although the clinical evaluation methodology for radiopharmaceuticals is still being developed, study results suggest that international harmonization of the regulatory systems and manufacturing controls for positron emission tomography drugs will be important for the development of such drugs in multinational countries, including Japan.

Keywords

radiopharmaceutical imaging positron emission tomography regulatory science drug approval

Introduction

Progress in life science technologies (molecular biology, pharmacogenomics, proteomics, etc) has made the detection of individual diseases more strategic and has led to the development of “personalized medicine”—treatments based on a person’s individual characteristics. In recent years, however, drug development has become less productive and new drug development more difficult. In this more challenging environment, more effective therapies that include companion diagnostic test kits have been attracting attention as one method for accelerating new drug approval.¹ Although new drug development is a highly uncertain endeavor, it is expected that the use of biomarkers can reduce the level of uncertainty and improve the benefit-risk balance for individual patients.²

In addition to detection through the use of ex vivo diagnostic agents, another approach has been attracting attention in recent years: the use of molecular imaging to detect proteins inside the body. Although molecular imaging technology is still being assessed as a means of diagnosing disease, functional diagnosis—in which biological or molecular chemical functions are measured with positron emission tomography (PET) or single-photon emission computed tomography—is believed to be necessary for prompt diagnosis and to assess the efficacy or safety of a drug product. It is expected that this technology will lead to the development of personalized medicine in which the functional abnormalities present in diseases are assessed with imaging biomarkers, making it possible to select the patients that are the most appropriate for the therapeutic drug.

In the West, a PET drug with high affinity for beta-amyloid protein, a biomarker for Alzheimer dementia, has been approved as an “beta-amyloid protein functional diagnostic agent.”³ In Japan as well, beta-amyloid protein PET agents have been incorporated into anti-amyloid antibodies and gamma-secretase inhibitors, and this kind of PET imaging has started being used as a surrogate endpoint for assessing clinical efficacy.

Three FDA guidances were issued in the US in 2004 on the development of medical imaging drugs: “Part 1: Conducting Safety Assessments,”⁴ “Part 2: Clinical Indications,”⁵ and “Part 3: Design, Analysis, and Interpretation of Clinical Studies.”⁶ In Japan as well, guidelines were issued in 2012 on the clinical assessment of diagnostic radiopharmaceuticals, and standard clinical assessment methods have been presented for use when developing diagnostic radiopharmaceuticals.⁷

However, there have as yet been no reports of a detailed comparison of the approval statuses of radiopharmaceuticals in Japan and the US, and an analysis of the similarities and differences of radiopharmaceuticals in Japan and the US is believed to be important for the international development of future imaging biomarkers. In this study, we investigated the approval statuses of radiopharmaceuticals in the US and Japan based on the information provided in their package inserts, and we examined their similarities and differences, taking into account the different regulatory systems of the 2 countries.

Materials and Methods

The approval statuses of radiopharmaceuticals in Japan were investigated for products classified under the therapeutic category “radiopharmaceuticals” based on the drug product package information accessible on the Pharmaceuticals and Medical Devices Agency (PMDA) website.⁸ The background of approval for each product was investigated by examining the review reports, which are available from a different section of the same website.⁹ For information on US radiopharmaceuticals, we searched the FDA website for radiopharmaceuticals containing fluorine-18 (F-18), gallium-67 (GA-67), iodine-125 (I-125), iodine-123 (I-123), iodine-131 (I-131), indium-111 (IN-111), krypton-81 (KR-81), strontium-89 (SR-89), technetium-99 m (TC-99), thallium-201 (TH-201), xenon-133 (XE-133), chromium-51 (CR-51), or yttrium-90 (Y-90), which are radiopharmaceutical isotopes listed in Japanese package inserts.¹⁰ We also searched the FDA website for radiopharmaceuticals containing carbon-11 (C-11), carbon-14 (C-14), nitrogen-13 (N-13), radium-223 (RA-223), rubidium-82 (RB-82), or samarium-153 (SM-153), which are the radiopharmaceutical isotopes of FDA-approved radiopharmaceuticals reported by Cardinal Health.¹¹

For information on Japanese regulation of PET drugs, we searched the websites of the PMDA,¹² the Japanese Society of Nuclear Medicine,¹³ and the Japan Radioisotope Association (JRIA).¹⁴ For information on US regulation of PET drugs, we searched the FDA website.¹⁵

Results

Approval Statuses of Radiopharmaceuticals in Japan and the US

The drug product package insert database accessible from the PMDA website contains 60 products of 36 types that are classified as radiopharmacueticals. In addition, 49 types of radiopharmaceuticals approved by the FDA were found through its website. Table 1 shows the approval year and indication of radiopharmaceuticals that were approved in Japan and the US.

Table 1.

Radiopharmaceuticals approved in the US and Japan.

	Active Ingredients	Purpose	Approval Year, US/Japan	Indications
C-11	Choline C-11	Diagnostic	2012/NA	PET imaging of patients with suspected prostate cancer recurrence and noninformative bone scintigraphy, CT, or MRI.
C-14	Urea C-14	Diagnostic	1997/NA	Indicated for use in the detection of gastric urease as an aid in the diagnosis of Helicobacter pylori infection in the human stomach.
CR-51	Sodium chromate CR-51	Diagnostic	1971/1985	US: Discontinued. Japan: Determination of (1) circulated blood volume and red cell volume and (2) red cell survival time.
F-18	Fludeoxyglucose F18	Diagnostic	1994/2005	Indicated in PET for abnormal glucose metabolism in oncology; myocardial hibernation; abnormal glucose metabolism associated with foci of epileptic seizures.
F-18	Sodium fluoride F 18	Diagnostic	2011/NA	Radioactive diagnostic agent for PET indicated for imaging of bone to define areas of altered osteogenic activity.
F-18	Florbetapir F-18	Diagnostic	2012/NA	PET imaging of the brain to estimate β-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer disease and other causes of cognitive decline.
GA-67	Gallium citrate GA 67	Diagnostic	1976/1991	Useful to demonstrate the presence/extent of Hodgkin disease, lymphoma, bronchogenic carcinoma; aids in detecting some acute inflammatory lesions.
I-123	Sodium iodide I-123	Diagnostic	1982/1979	US: Diagnostic procedure to be used in evaluating thyroid function and/or morphology. Japan: Diagnosis of thyroid disease by thyroid scintigraphy, evaluation of thyroid function.
I-123	Iofetamine I-123	Diagnostic	1987/1994	US: Discontinued. Japan: Scintigraphy of local cerebral blood flow.
I-123	Iobenguane sulfate I-123	Diagnostic	2008/1992	The detection of primary or metastatic pheochromocytoma or neuroblastoma as an adjunct to other diagnostic tests; scintigraphic assessment of sympathetic innervation of the myocardium.
I-123	Ioflupane I-123	Diagnostic	2011/2013	US, Japan: Striatal dopamine transporter visualization with SPECT brain imaging to assist in the evaluation of adult patients with suspected Parkinsonian syndromes. Japan: Dementia with Lewy bodies.
I-123	Iocanilidic acid I123	Diagnostic	NA/1993	Diagnosis of heart disease by fatty acid metabolism scintigraphy.
I-123	Iomazenil I-123	Diagnostic	NA/2004	Diagnosis of epilepsy focus.
I-125	Iothalamate sodium I-125	Diagnostic	1974/NA	Evaluation of glomerular filtration in the diagnosis or monitoring of patients with renal disease.
I-125	Albumin iodinated I-125 serum	Diagnostic	1976/NA	Indicated for use in the determination of (1) total blood and (2) plasma volume.
I-131	Albumin iodinated I-131 serum	Diagnostic	1976/1985	Indicated for use in determinations of the following: Japan, US: Total blood and plasma volumes, cardiac output, cardiac and pulmonary blood volumes and circulation times. US: Protein turnover studies, heart and great vessel delineation, localization of the placenta, localization of cerebral neoplasms.
I-131	3-Iodobenzylguanidine I-131	Diagnostic	1994/1993	US: Discontinued. Japan: Diagnosis of pheochromocytoma, neuroblastoma, and medullary thyroid cancer by scintigraphy.
I-131	Sodium iodide I-131	Therapeutic	2003/1990	US: Treatment of hyperthyroidism and selected cases of carcinoma of the thyroid. Japan: Treatment of hyperthyroidism, thyroid cancer and metastatic foci, and the identification of thyroid cancer metastatic foci by scintigraphy.
I-131	Tositumomab; iodine I 131 tositumomab	Therapeutic	2003/NA	Radiotherapeutic antibody indicated for the treatment of patients with CD20-positive, relapsed or refractory, low-grade, follicular, or transformed non-Hodgkin lymphoma who have progressed during or after rituximab therapy, including patients with rituximab-refractory non-Hodgkin lymphoma.
I-131	Norcholestenol iodomethyl I-131	Diagnostic	NA/1980	Diagnosis of the localization of adrenal gland disease by adrenal scintigraphy.
IN-111	Indium IN-111 pentetate disodium	Diagnostic	1982/NA	For use in radionuclide cisternography.
IN-111	Indium IN-111 oxyquinoline	Diagnostic	1985/1992	Indium IN-111 oxyquinoline–labeled leukocytes may be used as an adjunct in the detection of inflammatory processes to which leukocytes migrate, such as those associated with abscesses or other infection, following reinjection and detection by appropriate imaging procedures.
IN-111	Indium IN-111 chloride	Diagnostic / therapeutic	1992/2008	Radiolabeling of monoclonal antibodies in preparations used for in vivo diagnostic imaging procedures. Radiolabeling of Zevalin in preparations used for radio immunotherapy procedures.
IN-111	Indium IN-111 pentetreotide kit	Diagnostic	1994/NA	Agent for the scintigraphic localization of primary and metastatic neuroendocrine tumors bearing somatostatin receptors.
IN-111	Capromab pendetide	Diagnostic	1996/NA	Diagnostic imaging agent in newly diagnosed patients with biopsy-proven prostate cancer. Diagnostic imaging agent in postprostatectomy patients with a rising prostate-specific antigen and a negative or equivocal standard metastatic evaluation in whom there is a high clinical suspicion of occult metastatic disease.
N-13	Ammonia N-13	Diagnostic	2007/NA	Radioactive diagnostic agent for PET indicated for diagnostic PET imaging of the myocardium under rest or pharmacologic stress conditions to evaluate myocardial perfusion in patients with suspected or existing coronary artery disease.
RA-223	Radium RA-223 dichloride	Therapeutic	2013/NA	Alpha particle–emitting radioactive therapeutic agent indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease.
RB-82	Rubidium chloride RB-82	Diagnostic	1989/NA	Radioactive diagnostic agent indicated for PET imaging of the myocardium under rest or pharmacologic stress conditions to evaluate regional myocardial perfusion in adult patients with suspected or existing coronary artery disease.
SM-153	Samarium SM-153 lexidronam pentasodium	Therapeutic	1997/NA	Relief of pain in patients with confirmed osteoblastic metastatic bone lesions that enhance on radionuclide bone scan.
SR-89	Strontium chloride SR-89	Therapeutic	1993/2007	Relief of bone pain in patients with painful skeletal metastases.
TC-99	Technetium TC-99 M sodium pertechnetate generator	Diagnostic	1973/1984	US: Brain imaging, thyroid imaging, salivary gland imaging, placenta localization, blood pool imaging, urinary bladder imaging for detection of vesicoureteral reflux, and nasolacrimal drainage system imaging. Japan: Diagnosis of cerebral tumors, cerebrovascular disease, thyroid disease, disease of the salivary gland, and ectopic gastric mucosa disease.
TC-99	Technetium TC-99 M pyrophosphate kit	Diagnostic	1974/1979	Skeletal imaging agent used to demonstrate areas of altered osteogenesis and a cardiac imaging agent used as an adjunct in the diagnosis of acute myocardial infarction. Blood pool imaging agent that may be used for gated blood pool imaging and for the detection of sites of gastrointestinal bleeding.
TC-99	Technetium TC-99 M albumin aggregated kit	Diagnostic	1976/1977	Lung imaging agent that may be used as an adjunct in the evaluation of pulmonary perfusion in adults and children. Imaging agent to aid in the evaluation of peritoneovenous (LeVeen) shunt patency.
TC-99	Technetium TC-99 M pentetate kit	Diagnostic	1976/1979	US: Kidney imaging and brain imaging, to assess renal perfusion and to estimate glomerular filtration rate. Japan: Diagnosis of renal disease by renal scintigraphy.
TC-99	Technetium TC-99 M human serum albumin	Diagnostic	1977/1980	US: Discontinued. Japan: Diagnosis of heart disease by radioisotope angiography and cardiac pool scintigraphy.
TC-99	Technetium TC-99 M medronate	Diagnostic	1978/1978	US: Bone imaging agent to delineate areas of altered osteogenesis. Japan: Diagnosis of bone disease by bone scintigraphy, and cerebral tumor and/or cerebrovascular disease by brain scintigraphy.
TC-99	Technetium TC-99 M sulfur colloid kit	Diagnostic	1978/NA	Radioactive diagnostic agent indicated to assist in the (1) localization of lymph nodes draining a primary tumor in patients with breast cancer or malignant melanoma and (2) evaluation of peritoneovenous (LeVeen) shunt patency in adults. In adults and pediatric patients for (1) imaging areas of functioning reticuloendothelial cells in the liver, spleen, and bone marrow and (2) studies of esophageal transit and gastroesophageal reflux and detection of pulmonary aspiration of gastric contents.
TC-99	Technetium TC-99 M oxidronate kit	Diagnostic	1981/1982	Diagnostic skeletal imaging agent used to demonstrate areas of altered osteogenesis in adult and pediatric patients.
TC-99	Technetium TC-99 M succimer kit	Diagnostic	1982/1978	An aid in the scintigraphic evaluation of renal parenchymal disorders.
TC-99	Technetium TC-99 M disofenin kit	Diagnostic	1982/NA	Hepatobiliary imaging agent; diagnosis of acute cholecystitis as well as to rule out the occurrence of acute cholecystitis in suspected patients with right-upper-quadrant pain, fever, jaundice, right-upper-quadrant tenderness, and mass or rebound tenderness but not limited to these signs and symptoms.
TC-99	Technetium TC-99 M mebrofenin kit	Diagnostic	1987/NA	Hepatobiliary imaging agent.
TC-99	Technetium TC-99 M exametazime kit	Diagnostic	1988/1997	US, Japan: Adjunct in the detection of altered regional cerebral perfusion in stroke. US: Leukocyte-labeled scintigraphy as an adjunct in the localization of intra-abdominal infection and inflammatory bowel disease.
TC-99	Technetium TC-99 M sestamibi kit	Diagnostic	1990/1993	US: Myocardial perfusion agent indicated for detecting coronary artery disease. Planar imaging as a second-line diagnostic drug after mammography. Japan: Diagnosis of heart disease, heart function by first-pass ventriculography, and localization in hyperparathyroidism by parathyroid scintigraphy.
TC-99	Technetium TC-99 M mertiatide kit	Diagnostic	1990/1994	Renal imaging agent for use in the diagnosis of congenital and acquired abnormalities, renal failure, urinary tract obstruction, and calculi in adults and pediatric patients.
TC-99	Technetium TC-99 M red blood cell kit	Diagnostic	1991/NA	Technetium Tc 99m–labeled red blood cells are used for blood pool imaging, including cardiac first pass and gated equilibrium imaging and for detection of sites of gastrointestinal bleeding.
TC-99	Technetium TC-99 M bicisate kit	Diagnostic	1994/1994	Adjunct to conventional CT or MRI imaging in the localization of stroke in patients in whom stroke has already been diagnosed.
TC-99	Technetium TC-99 M tetrofosmin kit	Diagnostic	1996/1994	Scintigraphic imaging of the myocardium. Assessment of left ventricular function in patients being evaluated for heart disease.
TC-99	Technetium (99 m Tc) fanolesomab; neutrospec	Diagnostic	2004/NA	Scintigraphic imaging of patients ≥5 years of age with equivocal signs and symptoms of appendicitis.
TC-99	Technetium TC-99 M tilmanocept	Diagnostic	2013/NA	Radioactive diagnostic agent indicated for lymphatic mapping with a handheld gamma counter to assist in the localization of lymph nodes draining a primary tumor site in patients with breast cancer or melanoma.
TC-99	Technetium TC-99 M phytate	Diagnostic	NA/1977	(1) Diagnosis of hepatosplenic disease by hepatosplenic scintigraphy, (2) identification of sentinel lymph node and lymph scintigraphy in breast cancer and malignant melanoma.
TC-99	Technetium TC-99 M stannous colloid	Diagnostic	NA/1977	(1) Diagnosis of hepatosplenic disease by hepatosplenic scintigraphy, (2) identification of sentinel lymph node and lymph scintigraphy in breast cancer and malignant melanoma.
TC-99	Technetium TC-99 M N-pyridoxyl-5-methyltryptophan	Diagnostic	NA/1984	Diagnosis of hepatobiliary system disease and function.
TC-99	Technetium TC-99 M galactosyl human serum albumin diethylenetriamine pentaacetic acid	Diagnostic	NA/1992	Diagnosis of liver function and morphology.
TH-201	Thallous chloride TL-201	Diagnostic	1977/1991	Myocardial perfusion imaging with either planar or SPECT techniques for the diagnosis and localization of myocardial infarction. Conjunction with exercise stress testing as an adjunct in the diagnosis of ischemic heart disease. Localization of sites of parathyroid hyperactivity in patients. Preoperative screening to localize extrathyroidal and mediastinal sites of parathyroid hyperactivity and for postsurgical reexamination.
XE-133	Xenon XE-133	Diagnostic	1974/1979	Inhalation of xenon Xe 133 gas has proved valuable for the evaluation of pulmonary function and for imaging the lungs. It may also be used to assess cerebral flow.
Y-90	Ibritumomab tiuxetan	Therapeutic	2002/2008	Relapsed or refractory, low-grade or follicular B-cell non-Hodgkin lymphoma. Previously untreated follicular non-Hodgkin lymphoma that achieves a partial or complete response to first-line chemotherapy.

Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; NA, not approved; NHL, non-Hodgkin lymphoma; PET, positron emission tomography; SPECT, single photon emission computed tomography.

Radionuclide Type of Radiopharmaceuticals

The most common radiopharmaceuticals in both the US and Japan were TC-99 radiopharmaceuticals. In Japan, the next most common were I-123 (n = 6), I-131 (n = 4), and IN-111 (n = 2) radiopharmaceuticals; in the US, the next most common were IN-111 (5), I-123 (4), I-131 (4), and F-18 (3) radiopharmaceuticals. Although C-11, C-14, I-125, N-13, RA-223, RB-82, and SM-153 radiopharmaceuticals have been approved in the US, no such radiopharmaceuticals have yet been approved in Japan.

Applications for Radiopharmaceuticals

The most common approved radiopharmaceuticals are diagnostic radiopharmaceuticals, which account for 42 and 32 of the approved radiopharmaceuticals in the US and Japan, respectively. There are 6 therapeutic radiopharmaceuticals that have been approved in the US: sodium iodide (¹³¹I), tositumomab (¹³¹I), dichloride (²²³Ra), lexidronam (¹⁵³Sm), chloride (⁸⁹Sr), and ibritumomab tiuxetan (⁹⁰Y); of these, sodium iodide (¹³¹I), chloride (⁸⁹Sr), and ibritumomab tiuxetan (⁹⁰Y) have been approved in Japan as well.

Ibritumomab tiuxetan (⁹⁰Y) includes a method for measuring the distribution in the body of ibritumomab tiuxetan (¹¹¹In) for the purpose of predicting safety based on the accumulation of ibritumomab tiuxetan (⁹⁰Y). This is described in the US product insert from 2009 as well, but the description of the preadministration of ibritumomab tiuxetan (¹¹¹In) was removed from the 2011 package insert. In Europe, as in the US, the preadministration of ibritumomab tiuxetan (¹¹¹In) is currently not required.

Approval Years of Radiopharmaceuticals

In Japan, 29 of 36 radiopharmaceuticals were approved before 1994. However, in the 18 years since 1995, only 7 have been approved: fludeoxyglucose (¹⁸F), ioflupane (¹²³I), iomazenil (¹²³I), chloride (¹¹¹In), chloride (⁸⁹Sr), exametazime (^99mTc), and ibritumomab tiuxetan (⁹⁰Y). In the US, 16 radiopharmaceuticals have been approved since 1995.

Twenty radiopharmaceuticals have been approved only in the US and 7 only in Japan. Of the 7 products that have been approved only in Japan, 6 were approved before 1995.

Approval Status of PET Agents in Japan and the US

Five drugs are indicated for PET imaging in the US: florbetapir (¹⁸F), sodium fluoride (¹⁸F), fludeoxyglucose (¹⁸F), ammonia (¹³N), and chloride (⁸²Rb). However, in Japan, only fludeoxyglucose (¹⁸F) has been approved.

We investigated the background of approval (regulatory actions) of fludeoxyglucose (¹⁸F) in Japan and the US using the PMDA review reports (Table 2). Regulatory approval was obtained in 2001 under the “medical device” category for an ¹⁸F-FDG synthesizer and in 2005 for ¹⁸F-FDG as a radiopharmaceutical. In the US, by contract, ¹⁸F-FDG received regulatory approval in 1994.

Table 2.

History of regulatory actions for fludeoxyglucose (¹⁸F).

US	Japan
FDG-PET with home-brewed ¹⁸F-FDG was used for the evaluation of malignancy, coronary artery disease, epileptic seizures, etc, since the 1980s.	FDG-PET was approved as highly advanced medical technology in 1993.
¹⁸F-FDG was approved for the evaluation of foci of epileptic seizures in 1994.	Synthesis device of ¹⁸F-FDG was approved as medical device in 2001.
Federal register stated that additional clinical trials were not required for the indication of malignancy, coronary artery disease, and epileptic seizures in 2000.	FDG-PET with home-brewed ¹⁸F-FDG for the diagnosis of malignancy, coronary artery disease, and epileptic seizures was reimbursed by government in 2002.
	¹⁸F-FDG was approved as radiopharmaceutical drug for the evaluation of diagnosis of malignancy, coronary artery disease, and epileptic seizures in 2005.

Abbreviation: PET, positron emission tomography.

Florbetapir (¹⁸F) was approved by the FDA in 2012 as a radioactive diagnostic agent for PET imaging.³ Florbetapir (¹⁸F) is used to predict beta-amyloid neuritic plaque density in patients with cognitive impairment of Alzheimer disease or other cause. It was approved in Europe in 2013. In Japan, an application is being filed for a florbetapir (¹⁸F) synthesizer.

Comparison of Regulatory System for PET Agents in Japan and the US

Table 3 shows the guidances on PET drugs in the US and Japan. In Japan, there are 2 types of regulatory review processes for PET drugs: the drug approval process and the medical device approval process. In the US, there is no medical device approval process for PET drugs, but the FDA regulates the manufacturing of PET drugs in each facility and each PET drug under current good manufacturing practice (cGMP). In 2009, the FDA published regulations¹⁶ describing the cGMP standards that each manufacturer is to follow during the production of a PET drug, as well as guidance on PET drug cGMP.¹⁷ Under the requirements of section 121 of the Modernization Act, a new drug application or abbreviated new drug application must be submitted for any PET drug marketed for clinical use in the US. In Japan, since 1985, the JRIA has certified the PET drug as “established techniques” when its manufacturing technology was mature.¹⁸ Fifteen PET drugs have been certified under this system. However, the JRIA has decided to end the certification system for mature technology and has proposed that some other system is needed to reflect the current efforts at globalization and standardization.¹⁸

Table 3.

Guidances on PET drugs in the US and Japan.

US	Japan
Regulatory review process for PET drugs
FDA, “Guidance: PET Drug Applications—Content and Format for NDAs and ANDAs” (2011)¹⁹ FDA, “Compliance Program Guidance Manual, PET CGMP Drug Process and Preapproval Inspections/Investigations” (2011)²⁰ FDA, “Guidance: Investigational New Drug Applications for Positron Emission Tomography (PET) Drugs” (2012)²¹	Regulatory review is performed as “drug” or “medical device” category under the Pharmaceutical Affairs Act.
Good manufacturing practice
FDA, “Guidance PET Drugs: Current Good Manufacturing Practice (CGMP)” (2009)¹⁷ FDA, “Guidance PET Drugs: Current Good Manufacturing Practice (CGMP) (Small Entity Compliance Guide)” (2011)²² FDA, “Guidance: FDA oversight of PET Drug Products—Questions and Answers” (2012)²³ 21 CFR parts 210, 211, and 212¹⁶	JSNM, “Standard of PET Drugs for Clinical Research of Molecular Imaging: Standard for Manufacturing, Edition 2” (2013)²⁵ JSNM, “Standard of PET Drugs for Clinical Research of Molecular Imaging: Standard for In-Hospital Manufacturing” (2013)²⁶
Clinical evaluation
FDA, “Draft Guidance for Industry: Standards for Clinical Trial Imaging Endpoints” (2011)²⁴ FDA, “Guidance for Industry: Developing Medical Imaging Drug and Biological Products” (2004): “Part 1: Conducting Safety Assessment,”⁴ “Part 2: Clinical Indications,”⁵ and “Part 3: Design, Analysis, and Interpretation of Clinical Studies”⁶	MHLW, “Guideline on Clinical Evaluation for Diagnostic Radiopharmaceuticals” (2012)⁷

Abbreviation: JSNM, Japanese Society of Nuclear Medicine; MHLW, Ministry of Health, Labour, and Welfare; PET, positron emission tomography.

For clinical evaluation, the FDA issued guidance on developing medical imaging drugs and draft guidance on standards for clinical trial imaging endpoints. In Japan, guidelines on clinical evaluation were issued in 2012. These guidances on clinical evaluation in the US and Japan stress that the effectiveness of diagnostic radiopharmaceuticals should be demonstrated by accurate imaging information obtained from images and by clinical benefit of the information.

Discussion

We reviewed 36 types of radiopharmaceuticals listed in the drug product package insert database accessible on the PMDA website and 49 types of radiopharmaceuticals listed in the database accessible on the FDA website and compared the approval statuses of radiopharmaceuticals in Japan and the US. We found that TC-99 radiopharmaceuticals were the most common type of approved radiopharmaceuticals in both Japan and the US, accounting for at least 80% of diagnostic applications.

We found the following differences between Japan and the US. First, 7 radionuclide types have been approved in the US but not Japan. Second, since 1995, 16 radiopharmaceuticals have been approved in the US but only 7 in Japan. Last, since 1995, 11 radiopharmaceuticals have been approved in the US, but only 1 has been approved in Japan.

We therefore found that few radiopharmaceuticals have been approved in Japan in the past 18 years. The JRIA reported that the number of in vivo examinations with radiopharmaceuticals was decreasing and the number of PET examinations was increasing.²⁷ Fewer of approvals of radiopharmaceuticals might be due to decreasing numbers of in vivo examinations.

Regarding FDG-PET in particular, which is a commonly used radiopharmaceutical, the background of development in Japan was different from that in the US. In the US, ¹⁸F-FDG was approved as a drug product in 1994. In Japan, regulatory approval was obtained in 2001 under the “medical device” category for an ¹⁸F-FDG synthesizer, and regulatory approval was obtained in 2005 for ¹⁸F-FDG as a radiopharmaceutical. The JRIA reported that there were 36 PET facilities in 2002, whereas there were 295 PET facilities in 2012.²⁷ Of the 295 PET facilities, 48 sites engaged only in PET drug production; 87 sites engaged in both the PET drug production and the use of PET drug delivery; and 160 sites engaged only in PET drug delivery. In other words, regulatory approval as a radiopharmaceutical is important to enable the use of PET drugs and the spread of imaging technology.

Regarding the regulatory system on PET drugs in Japan and the US, unapproved drugs are used in the US, and the FDA is going to oversee PET drug production in the future. Currently, 12 PET drugs are listed in the US Pharmacopeia. Four PET drugs are approved by the FDA, but 8 are not.²⁸ In Japan, the number of PET drugs being used has been increasing, and the JRIA will end the verification system for PET drugs as a mature technology and transition to a more suitable system. In addition, the Japanese Society of Nuclear Medicine issued the guidance on manufacturing and quality control for PET drugs that is based on the FDA's cGMP guidance.

PET drugs are expected to be used in preemptive medicine as a tool for molecular imaging for early diagnosis. Florbetapir (¹⁸F) is an amyloid imaging drug that was approved in the US and European Union. It is expected to become a tool for the early diagnosis of Alzheimer disease. Although no definitive therapy for Alzheimer disease has been established, it is hoped that early Alzheimer disease can be diagnosed, enabling effective therapeutic intervention. In addition, since most clinical trials are conducted globally, the international harmonization of the regulatory systems and manufacturing control of PET drugs will be an important for developing PET drugs in multinational countries, including Japan.

Conclusions

There are high hopes for the use of radiopharmaceutical molecular imaging in the field of personalized medicine, and standard methods for the clinical evaluation of radiopharmaceuticals are being established in Japan and the US. We found the following differences between Japan and the US: First, there were 7 radionuclide types that have been approved in the US but not in Japan. Second, since 1995, 16 radiopharmaceuticals have been approved in the US but only 7 in Japan. Last, since 1995, 11 radiopharmaceuticals have been approved in the US but only 1 in Japan. In addition, we compared regulatory systems between Japan and the US and found that the international harmonization of regulatory systems and manufacturing control for PET drugs will be an important for developing PET drugs in multinational countries, including Japan.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. N.H. is an employee of Pfizer Japan Inc. Tokyo, Japan. A.A. declares no conflict of interest.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Global COE program, the Multidisciplinary Education and Research Center for Regenerative Medicine, and the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

References

Rubin

Gilliland

. Drug development and clinical trials-the path to an approved cancer drug. Nature reviews. Clin Oncol. 2012;9:215–222.

Burns

. Developing pharmacogenetic evidence throughout clinical development. Clin Pharmacol Ther. 2010;88:867–870.

Yang

Rieves

Ganley

. Brain amyloid imaging-FDA approval of florbetapir F18 injection. N Engl J Med. 2012;367:885–887.

US Food and Drug Administration. Guidance for industry: developing medical imaging drug and biological products. Part 1: conducting safety assessments. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078930.pdf. Accessed October 15, 2013.

US Food and Drug Administration. Guidance for industry: developing medical imaging drug and biological products. Part 2: clinical indications. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071603.pdf. Accessed October 15, 2013.

US Food and Drug Administration. Guidance for industry: developing medical imaging drug and biological products. Part 3: design, analysis, and interpretation of clinical studies. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071604.pdf. Accessed October 15, 2013.

Ministry of Health, Labour, and Welfare. Guideline on clinical evaluation for the diagnostic radiopharmaceutical drugs. http://www.pmda.go.jp/kijunsakusei/file/guideline/new_drug/houshasei-hyouka_guideline.pdf. Accessed October 15, 2013.

Pharmaceuticals and Medical Devices Agency of Japan. Drug labels information. http://www.info.pmda.go.jp/info/iyaku_index.html. Accessed October 15, 2013.

Pharmaceuticals and Medical Devices Agency of Japan. Drug approval information. http://www.info.pmda.go.jp/approvalSrch/PharmacySrchInit? Accessed October 15, 2013.

10.

Food and Drug Administration. Drug@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed October 15, 2013.

11.

Cardinal Health. FDA-approved radiopharmaceuticals. http://www.cardinalhealth.com/mps/wcm/connect/1bcdfc80447f1763b29ab77fc4070dc5/1NPS12016_FDA-approved+RPs+list+v.8_v3.pdf?MOD=AJPERES&lmod=-2031365804&CACHEID=1bcdfc80447f1763b29ab77fc4070dc5&lmod=-2032422625&CACHEID=1bcdfc80447f1763b29ab77fc4070dc5. Accessed October 15, 2013.

12.

Pharmaceuticals and Medical Devices Agency of Japan. Guidance, guideline. http://www.pmda.go.jp/kijunsakusei/guideline.html. Accessed January 3, 2014.

13.

Japanese Society of Nuclear Medicine. http://www.jsnm.org/. Accessed January 3, 2014.

14.

Japan Radioisotope Association. http://www.jrias.or.jp/. Accessed January 3, 2014.

15.

US Food and Drug Administration. Development & approval process (drugs), manufacturing, positron emission tomography (PET). http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm085783.htm. Accessed January 3, 2014.

16.

US Food and Drug Administration. 21 CFR parts 210, 211, and 212, current good manufacturing practice for positron emission tomography drugs. http://www.gpo.gov/fdsys/pkg/FR-2009-12-10/pdf/E9-29285.pdf. Accessed January 3, 2014.

17.

US Food and Drug Administration. Guidance PET drugs: current good manufacturing practice (CGMP). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070306.pdf. Accessed January 3, 2014.

18.

Japan Radioisotope Association. http://www.jrias.or.jp/report/pdf/positron.pdf. Accessed January 3, 2014.

19.

US Food and Drug Administration. Guidance: PET drug applications—content and format for NDAs and ANDAs. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078738.pdf. Accessed January 3, 2014.

20.

US Food and Drug Administration

. Compliance program guidance manual: PET CGMP drug process and pre-approval inspections/investigations.

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM277416.pdf. Accessed January 3, 2014.

21.

US Food and Drug Administration. Guidance: investigational new drug applications for positron emission tomography (PET) drugs. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291573.pdf. Accessed January 3, 2014.

22.

US Food and Drug Administration. Guidance PET drugs: current good manufacturing practice (CGMP) (small entity compliance guide). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM266640.pdf. Accessed January 3, 2014.

23.

US Food and Drug Administration. Guidance: FDA oversight of PET drug products, questions and answers. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM290024.pdf. Accessed January 3, 2014.

24.

US Food and Drug Administration. Draft guidance for industry: standards for clinical trial imaging endpoints. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM268555.pdf#search='FDA+Standards+for+Clinical+Trial+Imaging+Endpoints. Accessed January 3, 2014.

25.

Japanese Society of Nuclear Medicine. Standard of PET drugs for clinical research of molecular imaging: standard for manufacturing, edition 2, 2013. http://www.jsnm.org/system/files. Accessed January 3, 2014.

26.

Japanese Society of Nuclear Medicine, Standard of PET drugs for clinical research of molecular imaging: standard for in-hospital manufacturing, 2013. http://jsnm.org/files/pdf/guideline/2013. Accessed January 3, 2014.

27.

Japan Radioisotope Association. http://www.jrias.or.jp/report/pdf/7th_kakuigakujitaityousa_2013_62_08_08.pdf. Accessed January 3, 2014.

28.

Schwarz

Norenberg

Berridge

. The future of USP monographs for PET drugs. J Nucl Med. 2013: 54:472–475.