The radiopharmaceutical industry and European Union regulations

After a brief historical introduction to Council Directives relating to the manufacture of radiopharmaceuticals the work of the Association of Radiopharmaceuticals Producers — Europe (ARPE) is discussed. ARPE has played a significant role as an officially recognized interlocutor with the EEC, influencing decisions on the registration of radiopharmaceuticals and labelling; this role is reviewed and difficulties identified. The future of radiopharmaceuticals is then considered; it is emphasized that harmonization of national laws by the European Council would represent a first step to enabling radiopharmaceutical manufacturers to access the largest possible market for their products.     

Radionuclides and radiopharmaceuticals for single-photon emission tomography, positron emission tomography and radiotherapy in Russia

The current status of the manufacture of radiopharmaceuticals for diagnostic and therapeutic application in Russia is discussed, consideration being given to various aspects of the production and distribution of radionuclides, radioisotope generators and kits as well as individual radiopharmaceuticals in different regions of the country. The major focus is on the recent developments in production technologies for therapeutic and single-photon emission tomography radionuclides, technetium chemistry and synthetic approaches for the labelling of compounds with short-lived positron emitters. The status of positron emission tomography and its application are considered. The major factors restricting the expansion of nuclear imaging techniques and radiotherapy in Russia are also discussed.     

Radionuclides and radiopharmaceuticals for single-photon emission tomography, positron emission tomography and radiotherapy in Russia.

The current status of the manufacture of radiopharmaceuticals for diagnostic and therapeutic application in Russia is discussed, consideration being given to various aspects of the production and distribution of radionuclides, radioisotope generators and kits as well as individual radiopharmaceuticals in different regions of the country. The major focus is on the recent developments in production technologies for therapeutic and single-photon emission tomography radionuclides, technetium chemistry and synthetic approaches for the labelling of compounds with short-lived positron emitters. The status of positron emission tomography and its application are considered. The major factors restricting the expansion of nuclear imaging techniques and radiotherapy in Russia are also discussed.     

Guidance on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals

This guidance is meant as a guidance to Part B of the EANM “Guidelines on Good Radiopharmacy Practice (GRPP)” issued by the Radiopharmacy Committee of the EANM (see www.eanm.org), covering the small-scale “in house” preparation of radiopharmaceuticals which are not kit procedures. The aim is to provide more detailed and practice-oriented guidance to those who are involved in the small-scale preparation of, for example, PET, therapeutic or other radiopharmaceuticals which are not intended for commercial purposes or distribution.     

Medicina nuclear y radiofármacos

Nuclear Medicine is a medical specialty that allows modern diagnostics and treatments using radiopharmaceuticals original radiotracers (drugs linked to a radioactive isotope). In Europe, radiopharmaceuticals are considered a special group of drugs and thus their preparation and use are regulated by a set of policies that have been adopted by individual member countries. The radiopharmaceuticals used in diagnostic examinations are administered in very small doses. So, in general, they have no pharmacological action, side effects or serious adverse reactions. The biggest problem associated with their use are the alterations in their biodistribution that may cause diagnostic errors.Nuclear Medicine is growing considerably influenced by the appearance and development of new radiopharmaceuticals in both the diagnostic and therapeutic fields and primarily to the impact of new multimodality imaging techniques (SPECT-CT, PET-CT, PET-MRI, etc.). It's mandatory to know the limitations of these techniques, distribution and eventual physiological alterations of radiopharmaceuticals, contraindications and adverse reactions of radiological contrasts, and the possible interference of both.     

An update on therapeutic uses of radiotracers in neoplastic disease

The key to delivering radiation to a lesion by means of internally administered radiopharmaceuticals is specificity of localization (a high lesion-background ratio). Factors that may limit this localization are pointed out. Potential alteration of the residence time within the lesion and use of radiation-sensitizing agents may bring new applications for radionuclides in therapy. The most common therapeutic applications of radiopharmaceuticals are outlined.     

Nuclear medicine and cardiology: the position of the Union of European Medical Specialists/Section of Nuclear Medicine

This paper summarizes a communication presented at the Second International Conference of Nuclear Cardiology, held in Cannes on 23–26 April 1995. The general evolution of nuclear medicine in Europe is examined within the context of European Union Directives, and the role of the Union of European Medical Specialists/Section of Nuclear Medicine is discussed. Thereafter consideration is given to the technical aspects of cardiovascular nuclear medicine procedures, and the situation with respect to such procedures in European countries is examined. In most European countries, nuclear medicine is a recognized specialty, while nuclear cardiology does not exist in its own right. In general, only nuclear medicine specialists have the responsibility for radionuclide studies, and most cardiovascular studies are performed under the direct responsibility of a licensed nuclear medicine specialist.     

The good laboratory practice and good clinical practice requirements for the production of radiopharmaceuticals in clinical research

Radiopharmaceuticals account for more than 95% of the group of sterile pharmaceutical products and should therefore be handled and produced with care. Since the introduction of the European directive, all pharmaceuticals used in clinical studies must be prepared under good manufacturing practice (GMP) conditions. This review aims to give an overview of the basic principles and guidelines for the preparation of radiopharmaceuticals. Special attention is given to the production area environment and personnel, the two basic requirements for GMP productions. Especially for the production area, two philosophies have to be combined: the cascade system of over-pressure for the production of pharmaceuticals and the under pressure system for the manufacturing of radioisotopes. Personnel should be selected based on education and regularly given special training for the handling of radioactive material. Compared to pharmaceuticals, radiopharmaceuticals have their own labels, taking into account their specific nature. Besides the standard quality control, other items for quality control of radiopharmaceuticals are also discussed in this article.     

Radiopharmaceutical maladministrations in New South Wales

BACKGROUND: Errors in medicine are being increasingly highlighted. There is potential for harm in nuclear medicine. AIM: To evaluate the frequency, type, causes and adverse effects of nuclear medicine radiopharmaceutical maladministrations reported to the New South Wales Environment Protection Authority. METHODS: We reviewed reports received by the New South Wales Environment Protection Authority over a 5-year period. The number and type of maladministrations, contributing factors and any adverse effects were recorded. Comparison was made with the total number of medicare-paid diagnostic and therapeutic nuclear medicine services undertaken in New South Wales for the same period. RESULTS: Fifty-seven maladministrations were reported to the New South Wales Environment Protection Authority. There were 666 179 nuclear medicine procedures recorded in New South Wales for the same period. Of the 57 reported maladministrations, the majority (n=34; 61%) were a result of incorrect radiopharmaceutical dispensing. Incorrect reading of labels attached to the syringe (n=8; 14%) and incorrect patient identification (n=7; 12%) accounted for most of the rest of the accidents. Most (n=48; 84%) involved 99mTc-based radiopharmaceuticals for diagnostic use, with three cases involving I for therapeutic use. In 96% of cases - those which involved diagnostic radiopharmaceuticals - there were no immediate adverse clinical outcomes. However, one subject developed unintended hypothyroidism as a result of the maladministration of 131I for therapy. CONCLUSION: Nuclear medicine maladministrations in New South Wales are uncommon, with approximately 8-9 incidents per 100 000 procedures. Most maladministrations are the consequence of incorrect radiopharmaceutical dispensing. All those which involved diagnostic radiopharmaceuticals resulted in no immediate adverse effects from the radiation exposure.     

PET radiopharmaceuticals in Europe: Current use and data relevant for the formulation of summaries of product characteristics (SPCs)

The increasing use of radiopharmaceuticals for positron emission tomography (PET) has come to the attention of regulatory bodies. In order to help authorities in all aspects, the EANM has formed a task group for licensing PET radiopharmaceuticals; this group has surveyed the use of these compounds in Europe by a questionnaire. The number of PET centres that responded to the questionnaire was 26, which included more than 90% of the larger European PET centres. The survey showed that 2-[¹⁸F]fluoro-2-deoxyglucose is by far the most important PET radiopharmaceutical with more than 200 applications per week, followed by [¹⁵O]water, [¹⁵O]carbonmonoxide, [¹³N]ammonia, [¹¹C]-l-methionine, andl-6-[¹⁸F]fluoro-DOPA. More than 25 other PET radiopharmaceuticals are in regular use, however, at rather low application frequencies. The data were used by the European Pharmacopoeia Commission for its priority rating for requesting the formulation of monographs. Since it is likely that group registrations will be issued by authorities for the PET radiopharmaceuticals, relevant data on toxicity and dosimetry for the formulation of summaries of product characteristics have been collected by the task group as well.     

The development of new radiopharmaceuticals

The development of new radiopharmaceuticals is the basis of the continuing growth of nuclear medicine. Chemical interactions of electron clouds in their three dimensional conformations bring together, in the process of molecular recognition, the reaction of antibody and antigen, receptor and ligand, enzyme and substrate, hormone and response site. This convergence enables the computer design of molecules such as ligands to fit computer-displayed conformational models showing active centres, positive and negative charges and other interactions. Indeed, given a particular molecule, a complementary binding structure can be devised. The hybridoma approach to monoclonal antibody production is being superceded by the bacterial bioengineer. The gene for the hypervariable region from the spleen cells of immunized mouse can be coupled with the myeloma gene. The polymerase chain reaction can duplicate the DNA a million times over in 20 min and the result transfected into a bacterial plasmid to produce the antibody. These scientific problems are soluble in principle and are being solved. However, so much damage to this developing biological field is being done by regulatory authorities that one must ask who should or can regulate the regulators. These problems have to be overcome in order to provide the new radiopharmaceuticals that are the food and wine of nuclear medicine.Invited lecture: To the European Association of Nuclear Medicine Congress, 1989, Strasbourg, France     

Teletherapy and radiopharmaceutical therapy of painful bone metastases

Bone pain from metastatic disease is most common in cancers of the breast, prostate, and lung. Despite the World Health organization algorithm for treating such pain, the outcomes are not often satisfactory. In 2005, there will be 3 radiopharmaceuticals available in the United States that can reduce or relieve bone pain caused by osteoblastic metastases with apparently equal efficacy. Phosphorus-32 as sodium phosphate, strontium-89 ( 89Sr) as the chloride, and samarium-153 lexidronam may all be given intravenously (and 32P also orally) in patients where bone scintigraphy demonstrates a metastatic lesion causing the patient's bone pain. Side effects are usually mild and include pancytopenia with leukocyte and platelet nadirs at approximately 50% of baseline, and a mild-to-moderate, but brief, increase in pain ("flare") in approximately 10% of patients. At least 1 of these radiotracers, 89Sr, has the availability to reduce the incidence of new bone metastases as well, but, given alone, none prolong life. In a few studies in which 89Sr has been combined with chemotherapy, prolongation of patient survival has been demonstrated. Many questions remain as to the optimization of use of this group of radiopharmaceuticals, including whether combinations of radiopharmaceuticals with each other, with bisphosphonates or with chemotherapy can improve the therapeutic outcomes even more.     

Needs for radioactivity standards and measurements in the life sciences.

For almost 100 years, radioactivity has been one of the major tools in medicine. Therapeutic applications that began with 226Ra and 222Rn implants have rapidly grown to include about 20 radionuclides with radiations specifically chosen to treat at different depths in tissue--ranging from a few millimeters for intravascular therapy to a few centimeters in the case of large solid tumors. Systemic treatments with radiopharmaceuticals have grown from the traditional 131I to more than ten candidate nuclides which are to be labeled to tumor-specific radiopharmaceuticals. Diagnostic radiopharmaceuticals are used in over 13 million procedures in the United States annually. About 40 nuclides are under investigation for these applications including single photon emitters for SPECT (single photon emission computed tomography) and positron emitters for PET (positron emission tomography). In addition to the mainstays of therapeutic and diagnostic radiology, radionuclides are widely used for in vitro tracers in the life sciences and represent one of the main tools in the field of molecular biology.     

Radiation dosimetry in nuclear medicine.

Radionuclides are used in nuclear medicine in a variety of diagnostic and therapeutic procedures. A knowledge of the radiation dose received by different organs in the body is essential to an evaluation of the risks and benefits of any procedure. In this paper, current methods for internal dosimetry are reviewed, as they are applied in nuclear medicine. Particularly, the Medical Internal Radiation Dose (MIRD) system for dosimetry is explained, and many of its published resources discussed. Available models representing individuals of different age and gender, including those representing the pregnant woman are described; current trends in establishing models for individual patients are also evaluated. The proper design of kinetic studies for establishing radiation doses for radiopharmaceuticals is discussed. An overview of how to use information obtained in a dosimetry study, including that of the effective dose equivalent (ICRP 30) and effective dose (ICRP 60), is given. Current trends and issues in internal dosimetry, including the calculation of patient-specific doses and in the use of small scale and microdosimetry techniques, are also reviewed.     

Recommendations for fluorine-18 production

Data for the production of fluorine-18 (t_1/2 = 109.6 min; β⁺ = 100%) are reviewed. The experience of some well-established European centres for positron emission tomography (PET), in the routine production of fluorine-18 for the purpose of labelling radiopharmaceuticals, is described. This experience is evaluated, along with published data, to give practical and technical recommendations to new PET group entering this key area.     

Metaiodobenzylguanidine and somatostatin in oncology: role in the management of neural crest tumours

Two recently developed radiopharmaceuticals, iodine-131 metaiodobenzylguanidine (MIBG) and indium-111 pentetreotide, are currently being used for the diagnosis and therapy of neural crest tumours by interaction with the characteristic features of these tumours, such as an active uptake-I mechanism at the cell membrane and the presence of vesicles or neurosecretory granules in the cytoplasm and of specific receptors at the cell membrane. This review focusses on the role of MIBG and somatostatin analogues in the management of neural crest tumours. A number of aspects of both tracers are compared and the cumulative results are reviewed. Other uses of these radiopharmaceuticals are mentioned. It is concluded that both ¹¹¹In-pentetreotide and ¹²³I/¹³¹-MIBG are sensitive indicators of neural crest tumours, and have a complementary role. Unlike MIBG, ¹¹¹In-pentetreotide is not specific for neural crest tumours, as scintigraphy is also positive in many other tumours, granulomas and autoimmune diseases. ¹³¹I-MIBG is effective in the therapy of several neural crest tumours; the biodistribution of ¹¹¹In-pentetreotide at present does not allow radionuclide therapy using a beta-emitting label. However, as an indicator of somatostatin receptors, ¹¹¹In-pentetreotide scintigraphy may be a predictor of response to palliative treatment with unlabelled octreotide. Recommendations for the use of these procedures are given.This paper was presented at the European Association of Nuclear Medicine Congress 1993, in Lausanne (Switzerland).     

Anaphylactic reaction to orthoiodohippurate

A case of an anaphylactic reaction following administration of ¹²⁵I- and ¹³¹I-o-iodohippurate in a 32-year-old woman is reported. The patient had a renography performed because of hematuria. She was known to react to an intravenous pyelography previously performed with an anaphylactic shock. The importance of reporting all adverse reactions to radiopharmaceuticals for central registration is stressed.     

EANM guideline for the preparation of an Investigational Medicinal Product Dossier (IMPD)

The preparation of an Investigational Medicinal Product Dossier (IMPD) for a radiopharmaceutical to be used in a clinical trial is a challenging proposition for radiopharmaceutical scientists working in small-scale radiopharmacies. In addition to the vast quantity of information to be assembled, the structure of a standard IMPD is not well suited to the special characteristics of radiopharmaceuticals. This guideline aims to take radiopharmaceutical scientists through the practicalities of preparing an IMPD, in particular giving advice where the standard format is not suitable. Examples of generic IMPDs for three classes of radiopharmaceuticals are given: a small molecule, a kit-based diagnostic test and a therapeutic radiopharmaceutical.     

A new payment system for outpatient services? The implications for radiology

Congress is now contemplating the most significant change in outpatient payment methodology in Medicare's 31-year history. It may approve a proposal by the Health Care Financing Administration (HCFA) to establish a Medicare prospective payment system for hospital outpatient departments. In March 1955, five years after a Congressional directive to develop a new outpatient payment system, HCFA delivered its proposal recommending use of the ambulatory patient groups (APG) classification system for determining payment of hospital outpatient services. The APG system, which uses outpatient procedures as its primary variable, divides all such procedures into one of three categories: 1) significant procedures or therapies (including therapeutic and other significant radiological procedures); 2) ancillary test and procedures (including 11 radiology ancillary service APGs); or 3) medical visits. Outpatients can be assigned to one or more of the 290 APGs, each comprising a number of clinically and resource intensity-similar procedures, medical visits or ancillary tests. Any new payment methodology for outpatient procedures would broadly impact the radiology community. How radiology providers will fare under the system being proposed will depend on several issues that have not yet been resolved, such as how the basic unit of payment is defined (e.g., a service, a visit, or an episode of care) and whether payment rates will be adequate to compensate for the costs of providing services. One key issue will be whether contrast media and radiopharmaceuticals will continue to be paid as pass-through costs, giving providers the flexibility to choose the specific agent that is most appropriate for their patients.     

A survey of radiation synovectomy in Europe, 1991–1993

The prevalence of radiation synovectomy practice is unknown. As new particulate radiopharmaceuticals offering many potential advantages are being developed, it seems prudent to appraise the extent, frequency and variation in radiation synovectomy practice. We have evaluated radiation synovectomy practice in Europe over the period 1991–1993 by means of a postal questionnaire. More than 2300 European members of the European Association of Nuclear Medicine were questioned about the number of treated patients and joints, disease prevalence in their patients and the use of radio-pharmaceuticals. Overall, 119/490 (24%) of centres replying to the survey practised radiation synovectomy during the 3 years. There were 13 450 different joint injections in 8578 patients. Rheumatoid arthritis was the most prevalent disease in patients treated (71%) and the most frequently treated joints were knee (46%) and finger joints (20%). Eight different radiopharmaceuticals were employed. Yttrium-90 colloids were most frequently and widely (100/119 centres) used, mainly employed for knee synovectomy but were also used to treat most appendicular joints. Erbium-169 colloid was almost exclusively used to treat finger joints (31/33 centres). Corticosteroid was routinely co-injected in 36/60 (60%) centres. Radiation synovectomy was widely practised throughout Europe during 1991–1993. There are variations in practice illustrated by the diversity of treated arthritides and injected joints and by the use and application of different radiopharmaceuticals.