In this issue of the European Journal of Nuclear Medicine and Molecular Imaging, the
article by Antunes et al., entitled “Are radiogallium-labelled DOTA-conjugated somatostatin
analogues superior to those labelled with other radiometals?”, provides another example
of the high potential of the 68Ge/68Ga generator for PET applications in nuclear medicine.
The use of 68Ge/68Ga generators in nuclear medicine is very attractive for several
reasons:
The 270-day half-life of the parent 68Ge allows use of the generator for a long period,
potentially up to 1 year or even longer.
The 68-min half-life of 68Ga matches the pharmacokinetics of many peptides and other
small molecules owing to rapid diffusion, localisation at the target and fast blood
clearance.
The PET radionuclide68Ga is continuously available at a reasonable cost from a 68Ge/68Ga
generator, including for centres without a cyclotron.
Besides the DOTA analogues of somatostatin [1–5], DOTA-derivatised analogues of several
other interesting peptides have been developed, such as bombesin [6–10], substance
P [11, 12], neurotensin [13] and CCK [14–16]. DOTA is an excellent ligand for binding
of gallium; as a consequence, DOTA-peptides can be rapidly and efficiently labelled
with 68Ga at high specific activities [10, 17, 18], which implies that the mass of
peptide to be administered can be very low [6, 19, 20]. This is of particular interest
in the case of peptides with potential pharmacological side-effects, including substance
P, bombesin and CCK.
In addition, labelling with 68Ga is not restricted to DOTA-derivatised compounds.
As long ago as the 1970s and 1980s, several 68Ga-labelled tracers were reported, e.g.
for haematological applications and for investigations of myocardial, liver and kidney
function [21–29], but the lack of a reliable source of the radionuclide prohibited
their further development. It can be expected that the commercial availability of
68Ge/68Ga generators will stimulate radiochemists and radiopharmacists to develop
new68Ga-based radiopharmaceuticals for PET application; hence the number of potential
68Ga tracers for clinical applications is very likely to expand in the near future.
On the other hand, despite these encouraging prospects and the favourable results
of recent clinical studies using 68Ga-labelled peptides, there is still quite a long
way to go before 68Ga-labelled compounds become standard radiopharmaceuticals for
widespread use in daily nuclear medicine routine. The reason for this has to be sought
mainly in the requirements imposed by pharmaceutical legislation. Thus far, no company
has a marketing authorisation for a 68Ge/68Ga generator. Such a marketing authorisation
is a strict requirement for a radionuclide generator from which is produced a daughter
radionuclide that is to be obtained by elution and used in a radiopharmaceutical,
as clearly stated by Directive 2001/83/EC of the European Parliament and of the European
Council, art. 6.2 (November 6, 2001) on the community code relating to medicinal products
for human use. Among many other requirements, such as those relating to establishment
of chemical, radiochemical and radionuclidic purity of the eluate, the granting of
a marketing authorisation for a 68Ge/68Ga generator is dependent on the condition
that it is manufactured under conditions of good manufacturing practice (GMP). Indeed,
the eluate of such a generator is to be considered as an active substance used as
a starting material for a medicinal product for human use. Article 46 (f) of European
Directive 2001/83/EC and Article 50 (f) of Directive 2001/82/EC, as amended by Directives
2004/27/EC and 2004/28/EC respectively, place new obligations on manufacturing authorisation
holders to use only active substances that have been manufactured in accordance with
GMP for starting materials [30]. To the best of our knowledge, no such GMP-produced
generator is yet available on the European market, although some companies seem to
be exploring the idea. In this respect, a clear expression of interest from the nuclear
medicine community may help to speed up decisions in companies’ headquarters and the
necessary extensive preparatory work.
Apart from the need for an authorised 68Ga generator of “medicinal quality”, the use
of 68Ga-labelled agents as radiopharmaceuticals is dependent on many conditions, rules
and laws. The simplest and most straightforward way to permit the use of such tracers
in an authorised way would be for a manufacturer of medicinal products to obtain a
marketing authorisation for one or more labelling kits for the preparation of 68Ga-labelled
radiopharmaceuticals and to make these kits available on the market. As is the case
for the development of any new diagnostic or therapeutic drug, this work would take
many years and cost millions of euros, requiring the elaboration of a complete dossier,
including optimisation of manufacturing and analytical methods, establishment of pharmacological
and radiation safety and extensive clinical studies to demonstrate the real clinical
value and profit. In the most optimistic view, it would take at least 5 years for
an approved 68Ga radiopharmaceutical or labelling kit to become commercially available.
As an alternative, and in view of the several promising literature reports on the
clinical benefit of 68Ga-labelled peptides for specific and sensitive diagnosis of
some pathologies (see above), one could argue that a medical doctor might rely on
his or her therapeutic (and diagnostic) freedom of choice, one of the main elements
of the medical profession, and thus might exercise personal responsibility to use
any (radioactive) compound that he or she judges useful for the welfare of the patient.
This argument is valid and in principle allows much earlier use of interesting new
medicinal products, especially in the case of tracers of which only nanomolar amounts
have to be administered once or a few times, thus entailing minimal risks of toxicity
or side-effects. In this case, however, each 68Ga-labelled preparation would have
to be considered as a magistral or officinal preparation, subject to the restrictions
and requirements of such preparations. A magistral preparation/product is defined
as any medicinal product, prepared in a pharmacy in accordance with a medical prescription
for an individual patient (commonly known as the magistral formula). An officinal
preparation/product is any medicinal product which is prepared in a pharmacy in accordance
with the prescriptions of a pharmacopoeia and is intended to be supplied directly
to the patients served by the pharmacy in question (commonly known as the officinal
formula) [31]. In view of the absence of pharmacopoeial monographs on 68Ga-labelled
compounds to date, the only possibility of using such tracers at present seems to
be in the form of a magistral preparation under the responsibility of the prescribing
physician.
In view of the above-described legal definitions, 68Ga-labelled tracers used as magistral
(or, in the future, officinal) preparations necessarily have to be made by or under
the responsibility of a (radio)pharmacist and only may be used for the patient(s)
served by the pharmacy in question. In addition, only starting materials produced
under GMP conditions by approved manufacturers of pharmaceutical ingredients may be
used [30]. This requires that the ligands for complexation of 68Ga, such as DOTATOC,
DOTANOC, DOTATATE and other gallium binding agents, must have a certificate of GMP
production. Moreover, they must be certified to meet the (purity) requirements described
in a pharmacopoeial monograph, or in the absence of such a monograph, a monograph
of the manufacturer approved by pharmaceutical authorities. Finally, the pharmacist
in charge of such a preparation has full responsibility for the quality of the final
radiopharmaceutical and thus should be able to rely on well-defined specifications
as described in a pharmacopoeial or otherwise approved monograph.
As already stated, there are not yet monographs in the European Pharmacopoeia (Ph.
Eur.) on the eluate of 68Ga generators, on ligands for complexation of 68Ga or on
final 68Ga-labelled radiopharmaceuticals. This means that every manufacturer of 68Ga
generators or 68Ga-binding ligands which are intended to be used in the preparation
of a radiopharmaceutical and every (radio)pharmacist responsible for a final 68Ga-labelled
radiopharmaceutical has to develop and receive approval for his own monograph(s).
Apart from the low efficiency of such dispersed efforts, there is the potential problem
of non-uniform requirements for these products throughout Europe.
In view of this situation, the initiative has already been taken to ask the European
Pharmacopoeia Commission to allow Ph. Eur. expert group 14 (group on radioactive compounds)
to start the development of Ph. Eur monographs on 68Ga solutions for labelling (the
eluate of a 68Ga generator), on DOTATOC as a first 68Ga-binding peptide and on 68Ga-DOTATOC
as a first 68Ga radiopharmaceutical. The existence of such monographs would significantly
facilitate the use of 68Ga radiopharmaceuticals as a magistral or officinal preparation
and also, over a longer time scale, the approval and granting of marketing authorisations
for the starting materials and 68Ga radiopharmaceuticals. The development of these
monographs could take quite some time, depending on the consensus on and complexity
of the required analytical methods for establishment of chemical, radiochemical, radionuclidic
and microbiological purity. However, input from radiopharmacists and radiochemists
already familiar with such preparations for clinical studies and willingness to share
information on analytical procedures and safety determinations might significantly
contribute to the efficiency of the process and speed it up.
New specific radiopharmaceuticals are cornerstones for the survival and strength of
nuclear medicine, but their development and the possibility of their early use are
compromised by a number of factors such as the complexity of pharmaceutical legislation
and regulations, the lengthy process of obtaining a marketing authorisation and in
some cases a limited return on investment. In the case of diagnostic radiopharmaceuticals,
the principle of magistral or officinal preparations may be a solution that allows
physicians and their patients more flexible and early access to valuable new tracers,
evidently only on the condition of sufficient guarantees for the safety of the patient
and the efficacy of the clinical investigations. This requires a common strategy,
disciplined adherence to basic pharmaceutical rules and a joint effort by all professionals
in the field, radiopharmacists, radiochemists and nuclear medicine physicians, to
prove and guarantee the safety, efficacy and purity of such agents. Under such conditions,
the further introduction of new 68Ga-labelled and other radiopharmaceuticals is a
realistic expectation and may constitute an important boost to our field.