“Two roads diverged in a wood and I took the one less travelled by, and that has made all the difference.” Robert Frost “The road not taken”

The clinical need for new radiopharmaceuticals and new targets has changed in recent years. More than 10 years ago, Schwaiger and Wester [1] emphasized the importance of the combination of new specific radiopharmaceuticals and ‘targeted therapy’ for the realization of personalized medicine. Those were the years of the ‘metabolic’ radiopharmaceuticals and of the major ‘clinical need’ related to the limited value of [18F]FDG for several oncologic diseases such as the detection and monitoring of prostate cancer.

The paper also identified some major hurdles for the further expansion of clinical application of radiopharmaceuticals: the role of pharmaceutical industries which rely on the possibility of patenting new radiopharmaceuticals developed by academia, and the regulatory environment related to radiopharmaceutical approval and obtaining marketing authorization.

The growing demand of radiopharmaceuticals, the economic interest aroused [2], especially in PRRT (Peptide Receptor Radionuclide Therapy) drugs has opened up new scenarios in a context that was already in turmoil due to new discoveries in PET radiopharmaceuticals for the diagnosis of prostate cancer [3] and aimed at studying innovative targets such as the various FAPIs (Fibroblast activated protein inhibitors) [4].

Thus, we are now experiencing a massive response of science to the various clinical needs on the one hand, and the difficulty to ensure best care and patient access by translating the above new findings into safe, cost effective and easily available new radiopharmaceuticals. And this is where the regulatory framework comes in, as ‘the road taken’ by main regulatory agencies has originally been “biased” and unable to recognize and account for peculiarities of radiopharmaceuticals, where healthcare establishments and academia have always played (and still plays) a unique role, compared classic, non-radioactive drugs.

“The Road Not Taken” is a Robert Frost poem that argues for the importance of our choices, both big and small, since they shape our journey through life. We can transpose this concept to the different “roads taken” by European National Agencies and the US Food and Drug Administration (FDA) to define and regulate the pathway of a radiopharmaceutical from discovery to approval.

As we wrote in a recent Editorial [5], confident that “the aim of philosophy is to show the fly the way out of the fly bottle”, as Ludwig Wittgenstein affirmed, we will try to apply a philosophical approach to follow the radiopharmaceutical along the different roads from clinical need to approval and clinical use, being always confident in the process of “understanding and interpretation”, as well as in the symbolization of the radiopharmaceutical as a “structured whole” [5] with two clear and defined components, chemistry and regulations.

Chemistry, and thus ‘science’, is one component of the “structured whole”. As said above, in the field of radiopharmaceuticals, the scientific development and the discovery of new molecules, took place, in most cases, in healthcare establishments and in the academy.

As a good example, the development of radiopharmaceuticals targeting PSMA receptor (e.g. [68Ga]Ga-PSMA-11), which then lead to the renaissance of the word and concept of theranostics, open a reflection on the philosophy of scientific knowledge, the epistemology.

The science seen from a purely positivistic point of view, that’s, science as the ultimate solution to any problems, unfailing and, hence, irrefutable, is in our opinion not sustainable. On the other hand, restriction on patient’s availability for new radiopharmaceuticals, often posed by excessive regulatory overload, should be of concern.

Any radiopharmaceuticals is not a definitive end point but will remain so until a new molecule, following the discovery of new mechanisms of action underlying tumour development and differentiation, will replace it.

One of the greatest epistemologists of the twentieth century, Karl Popper, argued against the positivistic idea, prevalent at that time, that a scientific theory must be proven true and irrefutable.

For Popper, the opposite is true: infallibility is not an attribute of scientific theories; the scientist must always expect to be rebutted. Confutability, e.g., the critical attitude that requires “a posteriori” empirical checks, becomes a fundamental requirement to uncover any weaknesses in the theory.

Science is, or at least should be, considered as critical, “certain” knowledge, but always until otherwise proven. There are very well-confirmed theories in physics, in biology and medicine but they should not, however, be understood as absolute truths. Just as Newton’s theory, the cornerstone of classical physics, was not absolute and was disproved by Einstein’s theory.

Even the father of american pragmatism Charles Sanders Pierce, many decades earlier, recognized that the essence of the scientific method is to know, in principle, its fallibility and to have, within itself, a criterion for judging and self-correcting.

In a passionate discussion with Ludwig Wittgenstein [6], who claimed that there were no philosophical problems but only logic puzzles, Popper argued that problems indeed exist, that solutions have to be found, and that solutions and outcomes would be, in any case, provisional.

Moreover, he emphasized the fundamental role of the applied methodology. Consider how, after a hundred years, with the pandemic explosion, the methodological aspect for constructive criticism in science is indeed more crucial than ever, since social media and platforms, despite the theoretical possibility of playing a positive role in promoting constructive criticism, actually largely contributed to the increase obsessive and misinformed criticism [7].

But coming back to our “core” interests, academy and nuclear medicine departments, represent (and we are proud of that) the ‘science’ part of the ‘structural whole’. A role that they played, especially in the field of PET radiopharmaceuticals, for decades, when it was not profitable for the industry neither manufacturing radiopharmaceuticals nor investing in research and development. And they should keep on playing, although the demand for radiopharmaceuticals has drastically increased and the opportunity of patenting new therapeutic radiopharmaceuticals represents a potentially interesting business for the pharmaceutical industry, as demonstrated by the taking over of product pipelines of smaller radiopharmaceutical companies by big pharma companies such as Novartis, that then entered for the first time into the market of radiopharmaceuticals [8]. Indeed, most of the more interesting precursors, notably for PRRT, have been patented by big pharma companies, and a significant part of the most promising radiopharmaceuticals cannot be prepared in hospital radiopharmacies anymore, due to regulatory constraints, thus reducing patient’s availability and increasing costs for public healthcare systems. Moreover, applications for independent, non-sponsored clinical trials will be dramatically reduced, with further long-term impact.

Applying a hermeneutic approach [5] to Directive 2001/83EC [9], which has been the main pharmaceutical related legislation act in the European Union for more than 20 years, the essential aim of any rules governing production, distribution and use of medicinal products must be to safeguard public health and the development of the pharmaceutical industry, also including specific indications for radiopharmaceuticals. As mentioned above, this has not entirely been achieved.

From a philosophical point of view, one can mention the triumph of ‘calculative thinking’ (Denken als rechnen) of which Heidegger [10] spoke about referring to the world completely under the dominion of technology, where man is not at all prepared for a radical change in technological thinking and is only capable of calculation, the only form of thought suitable for the purpose of maintaining this dominion.

A more philosophically ‘pragmatist’ approach was taken by the Dutch government with regard to the production of [177Lu]Lu-DOTATATE; due to the enormous gap between the price of hospital vs industrially prepared radiopharmaceutical as a consequence of its marketing approval and orphan drug designation by the European Agency of Medicines (EMA), the Dutch ministry of Health encouraged the continuation of in-house (magistral) preparation [8].

And here we come to the impact of the second component of the “structured whole”, represented by regulations, to the last mile of the radiopharmaceutical “road”, clinical studies, approval, and marketing authorization.

In the previous editorial [5], it was pointed out how a regulatory overload led to a decrease in the competitiveness of the European Union compared to other countries with a more flexible regulatory framework, such as the USA.

Is there therefore a real difference between EMA and FDA approach? In other words, are there two different ‘roads’ for radiopharmaceuticals, two different interpretations of the rules that bring from the discovery of new potentially useful molecules to their implementation in routine patients care?

The answer is definitely affirmative, also considering that, e.g. European directives leave room for their interpretation by Member States, resulting in significant differences in the use of radiopharmaceuticals, while the FDA is the only regulatory “source” in the USA. Such a different approach is evident in the interpretation of GMP regulations for the authorization of radiopharmaceutical production.

But the fundamental difference lies in a different cultural approach, an approach stemming from a profoundly different philosophical tradition, which has influenced many aspects of European and American thought.

Since the seventeenth century, European philosophy has been deeply influenced by rationalism.

Descartes, often considered as the father of modern philosophy and largely seen as one of the major responsible for the increased attention given to epistemology in the seventeenth century, laid the foundation of European rationalism, later advocated by Spinoza and Leibniz, and was later opposed by the empiricist school that characterized and profoundly influenced English thought.

The rise of early modern rationalism exerted a deep influence on modern Western thought, and we believe that many aspects are still present.

Characteristic of Descartes’ philosophy is the so-called ‘Cartesian doubt’.

In ‘Meditations on First Philosophy’, he asserted that “It took a long time since I’ve realized how many falsehoods I have believed to be true, and how dubious were the conclusions I have deduced. At least once in a lifetime these beliefs must be subverted and one must start again from the first foundations.”

Knowledge, in the Cartesian sense, means to know something beyond not merely all reasonable doubt, but ALL possible doubt; “methodological” skepticism serves the search for “the truth”.

Cartesian ‘methodical doubt’ has been regarded as the root of the modern scientific method and its presence is still recognized in the approach of European regulatory agencies. The English approach is different, being UK the home of empiricism, the school of philosophical thought that considered experience as the sole foundation of knowledge from an objective (and thus opposed to rationalism) and subjective point of view.

In the USA, as mentioned earlier, the cultural approach is quite different from Europe in that, as a fundamentally Anglo-Saxon country, it has developed a way of thinking that is itself an evolution of empiricism: the pragmatism.

Pragmatism (from Greek πράγμα, concrete fact) constitutes the first original contribution of the USA to western philosophy; it is the form that the classical tradition of English empiricism has assumed in contemporary philosophy.

The experience to which classical empiricism referred was essentially past experience. For pragmatism, experience is essentially openness to the future: the anticipatory and projective aspect characterizes it primarily.

From this point of view, a ‘truth’ is such not because it is comparable with the accumulated data of past experience but because it is susceptible to any “use” in future experience. The prediction of this use, the determination of its limits, conditions and effects, constitutes the ‘meaning’ of the truth itself. For instance, William James affirmed that “true” is all that will be most beneficial to the individual and to the society.

The principle of pragmatism, in a nutshell, is that concrete activity, meaning the behaviour in the social, political or scientific sphere directed toward the realization of a concrete endpoint, exercises primacy over abstract theoretical or ethical-moral activity. From William James’ point of view, beliefs that are useful for “action” become ‘true’.

It is quite evident how the higher number of clinical trials approved in the USA compared to Europe, the different strategy of the radiopharmaceutical approval process, the flexibility in accommodating new technologies/methodologies are the result of a hermeneutic process more oriented towards a pragmatist rationale, aimed at the action, rather than towards an interpretation that places ‘methodical’ doubt, Cartesian scepticism, as a tool to reach truth.

We certainly do not wish to cast doubt on a philosophical system that has been the foundation of European thought and a founding pillar of epistemology, nor do we wish to privilege empiricism/pragmatism, as the ‘ideal’ philosophical systems. We merely intend to highlight how in the specific application of the radiopharmaceutical ‘road map’, two different lines of thought can have an impact on real life.

Returning to Robert Frost, and to its poem, it can be argued that one road should certainly be taken. But it should not be the road most or least travelled by, but rather the road that leads most rapidly to the development of a radiopharmaceutical according to its importance for patient care, taking into account the scientific aspects, the clinical need, the chemistry and the mechanisms of action.

To keep balanced the components of the “structured whole”, the regulatory aspect should facilitate, in compliance with the parameters of quality, efficacy and safety, the possibility of introducing new radiopharmaceuticals to improve patient care. And the hermeneutic approach should not be geopolitical, linked to national or continental regulations, but should overcome, integrate, the philosophical background, and focus on patient’s benefit and on sustainability: if a therapy is not economically sustainable, it is of no real value for the patients. So, what has been said about Heidegger's calculating thinking, which permeates all Western thought, Europe and the USA, should be rethought with a less pessimistic view of technique, which is not our limit, but a tool: profit should not be the sole purpose of ‘technology’, of the pharma company.

But in a world suffering from an excess of ‘inequalities’, we should re-evaluate the thought, also this neo-pragmatist, of Richard Rorty [11], who argued that more important than a sterile striving towards objectivity was the concept of ‘solidarity’. Certainly, the limitation of the role of nuclear medicine/academy, due to an excessive application of the patent’s prerogatives does not go in the right direction.

We could conclude by mentioning a recent press release (November 28th, 2022) of the Swiss Medical Technology Association [12] on Parliament’s instructions to the Federal Council to adapt national laws, enabling Switzerland to accept medical devices with FDA approval for the welfare of its own population, overcoming the limitation to have only access to medical devices with an EU certificate. The press release title is: Politicians decide in favour of patient care. Pragmatism and speed are now essential.

This could be a sign to consciously choose the “road to take”.