**4. Workshop results**

sufficiently (therapeutically) effective or have adverse toxic effects. For targeted drug delivery there are two general approaches. Drugs can be released near the desired location in the body or drugs can be designed for active or passive targeting purposes. In both cases the application of nanotechnologies (devices and molecules) promises to contribute to targeted delivery.

The promise of targeted delivery is not entirely new. The concept of drug targeting is linked with Paul Ehrlich's idea of 'Zauberkugeln', 'magic bullets' introduced over a century ago. The 'magic bullet' refers to the idea of homing in on the target and being effective - in this case affecting only the diseased tissue. Work on what are now considered to be nanotechnology enabled drug delivery systems has evolved since the 1960s [27-29] – although not exclusively related to targeting. Systems which are currently labeled as 'nanovehicles' have existed for some time, such as liposomes and polymer micelles (1960s), nanoparticles and dendrimers (1970s) [30]. The connection with the term 'nano' can thus be considered as a relabeling of what

Loss of activity due to too rapid clearance of drugs. NDDS can reduce clearance and may enable use of lower

Insufficient drug absorption and intracellular penetration. NDDS can improve absorption through epithelium and

Considering the history of drug delivery systems, promises of the application of nanotech‐ nologies may not be very effective in mobilizing actors. According to Boyd [27] the claim that "advances in nanotechnology are stimulating a 'revolution' in colloidal drug delivery" should be reconsidered given evolutionary developments over the last decades. Available funding

Modified and expanded from Allen and Cullis [31] with items from Couvreur and Vauthier [32].

doses.

Enhancing drug solubility, e.g. by micelles and liposomes providing hydrophilic and –phobic environments.

Regulated drug release can reduce or prevent tissue

NDDS protect drugs from premature degradation and

Particulate character of NDDS lowers distribution and

NDDS can increase drug concentrations by passive and active targeting (EPR-effect, targeting ligands).

improve intracellular penetration and distribution.

e.g. virosomes and virus-like particles.

NDDS can be engineered to stimulate immune response,

damage by extravasation.

may enable use of lower doses.

helps to reduce side-effects.

**Pharmaceutical challenges Expected solutions from NDDS**

was already occuring.

510 Application of Nanotechnology in Drug Delivery

body.

\*

Difficult or unacceptable pharmaceutical format due to poor solubility or toxicities linked to particular excipients.

Undesirable side-effects caused by extravasation (e.g. by leakage) of drugs from diseased to surrounding tissues.

Loss of activity of drugs due to rapid breakdown in the

Undesirable side-effects due to too widespread distribution

Difficult or unacceptable excipients to stimulate immune

**Table 1.** Expectations of nanotechnology enabled drug delivery systems

Suboptimal therapeutic effects due to use of low concentration of drugs to reduce side-effects.

in the body affecting healthy tissues.

responses in case of vaccines.

#### **4.1. Preparing the interactive workshop**

To prepare for a CTA workshop on NDDS it is important to have a solid understanding of dynamics related to the development and introduction of these emerging technologies. To do so I addressed the pre-engagement requirements mentioned in section 2.2 Table 2 summarizes major findings in the pre-engagement phase. For an in-depth discussion of dynamics in the drug delivery sector, nanomedicine and pharmaceutical developments more generally, see also [1, 33-35].

For the organization of the drug delivery workshop I co-operated with two (regional) branch organizations. One of them was an association of companies, including large pharmaceutical companies, who develop new pharmaceutical products. The other organization was an association of companies and organizations involved in biotechnology, including pharma‐ ceutical applications. For the former, nanotechnology was not a central topic as it was not (yet) an important theme for its members. Its members are relatively little involved in R&D activities and therefore activities in this area are limited almost by definition as many nanotechnologies are still in a pre-clinical stage. For the other the situation is somewhat different. Biopharma‐ ceutical companies are likely to be interested in nanotechnologies considering the promises for (difficult) delivery of macromolecules such as siRNA.

<sup>2</sup> Mapping of dynamics linked to nanotechnologies and the drug delivery sector was completed by analyzing relevant reports, papers, conducting interviews and attending international conferences on nanomedicine. Interviews were conducted with experts in the field in order to map opportunities, challenges and dynamics. In addition, interviews were used to find out about existing activities to develop new framing conditions, rules and practices and attempts at coordination with respect to nanotechnologies and drug delivery systems [11].


contested) development paths. A consortium of researchers anticipated that demonstrating clinical value would convince investors in the added value of targeted drug delivery systems which would contribute to overcoming the current impasse. To do so the consortium focused on incremental improvements of carriers with which there was already a lot of experience with regarding safety and effectiveness. Another set of actors disagreed with this approach and anticipated that big steps were needed in order to fulfill the promises of nano-enabled drug delivery. This group of actors formed a more ambitious consortium working on theranostics. The scenario speculated that the eventual fate of the consortia was not so much determined by its technological achievements but due to contextual factors. Concerns about possible risks of nanotechnology enabled drug delivery systems and gaps between diagnostic and thera‐ peutic possibilities co-determined the fate of the two development paths. In the end the

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The two other scenarios explored initiatives which more directly worked on improving coordination across actors in the drug delivery sector. One of these scenarios described the formation of a broad platform involving material and pharmaceutical researchers, clini‐ cians and people from industry. Discussions and differences of opinion among the platform participants about how to co-ordinate technology developments and their future introduc‐ tion forces the platform to abandon the initial broad scope and focus on specific carrier systems. While the platform is successful in attracting a broad variety of stakeholders, including interested actors from outside the nanomedicine world, attempts at co-ordina‐ tion across the domain are met with criticisms. One of the co-ordination mechanisms proposed by the platform is a stage-gate model which articulates criteria for the develop‐ ment and clinical introduction of novel targeted medicines. According to critics the stagegate model is too restrictive: commercially uncertain, but potentially interesting and promising technologies are too quickly shifted aside – effectively constraining opportuni‐

The third scenario explored attempts at stimulation and co-ordination from the demand-side. An alliance of patient organizations, knowledge institutes and firms is forged with the general aim of stimulating demand for cancer medicines with little side-effects. The alliance develops a broad research programme and actively involves itself in political circles and decision processes on the restructuration of the health care system and reimbursement policies. The broad focus on stimulating demand for reduction of side-effects of medicines attracts various alternative technology solutions. Only with help with the reference to cancer medicines, nanoenabled targeted drug delivery system remain on the agenda within the research programme which is eventually funded. First clinical evidence suggests that complexity of cancer requires different forms of drug delivery systems which may be commercially less attractive because of limited market volumes. Involved patient organizations are disappointed and press for applications fitting their specific diseases. The push of the alliance for medicines with less sideeffects then starts to lose its momentum. The emphasis on cancers as the major disease area

To inform the participants a preparatory document was distributed one week before the workshop. This document contained: (1) a program of the meeting; (2) a short introduction

ambitious consortium was disbanded.

ties for breakthrough technologies.

now appears to be less effective to mobilize resources.

**Table 2.** Summary of pre-engagement drug delivery workshop

I expected that attracting workshop participants would be difficult. Large pharmaceutical companies might not be interested due to waiting games and the low priority for nanotech‐ nologies. Clinicians might not be interested, due to their limited involvement until now. It indeed proved difficult to attract participants from large pharmaceutical companies and, for that matter, biopharmaceutical companies, to attend the workshop on drug delivery - despite efforts by the co-organizing branche organizations. Nanotechnologies were not a high priority for potential participants and caution in discussing R&D developments were provided as important reasons for not attending the workshop. Attracting clinicians also proved to be difficult, albeit for different reasons. While some clinicians were interested in the phenomenon of nanotechnologies, but not able to attend due to busy schedules, others were sceptical about the value of nanotechnologies and not interested in participating in the workshop. These observations are relevant as they already give indications of possible difficulties in bringing about co-ordination in the field regarding emerging NDDS.

While eventually no clinicians or participants from large pharmaceutical companies attended, participants from different parts of the chain were present at the workshop, including some who had experiences with interactions with pharmaceutical companies and clinicians. Participants from knowledge institutes, suppliers of delivery systems, and a drug develop‐ ment firm were present. In addition, a firm involved with microsystem technologies and a governmental organization involved with nanotechnologies were present.

To prepare for the discussion and support participants thinking about current and future developments, three scenarios were crafted. One scenario explored two different (and contested) development paths. A consortium of researchers anticipated that demonstrating clinical value would convince investors in the added value of targeted drug delivery systems which would contribute to overcoming the current impasse. To do so the consortium focused on incremental improvements of carriers with which there was already a lot of experience with regarding safety and effectiveness. Another set of actors disagreed with this approach and anticipated that big steps were needed in order to fulfill the promises of nano-enabled drug delivery. This group of actors formed a more ambitious consortium working on theranostics. The scenario speculated that the eventual fate of the consortia was not so much determined by its technological achievements but due to contextual factors. Concerns about possible risks of nanotechnology enabled drug delivery systems and gaps between diagnostic and thera‐ peutic possibilities co-determined the fate of the two development paths. In the end the ambitious consortium was disbanded.

The two other scenarios explored initiatives which more directly worked on improving coordination across actors in the drug delivery sector. One of these scenarios described the formation of a broad platform involving material and pharmaceutical researchers, clini‐ cians and people from industry. Discussions and differences of opinion among the platform participants about how to co-ordinate technology developments and their future introduc‐ tion forces the platform to abandon the initial broad scope and focus on specific carrier systems. While the platform is successful in attracting a broad variety of stakeholders, including interested actors from outside the nanomedicine world, attempts at co-ordina‐ tion across the domain are met with criticisms. One of the co-ordination mechanisms proposed by the platform is a stage-gate model which articulates criteria for the develop‐ ment and clinical introduction of novel targeted medicines. According to critics the stagegate model is too restrictive: commercially uncertain, but potentially interesting and promising technologies are too quickly shifted aside – effectively constraining opportuni‐ ties for breakthrough technologies.

I expected that attracting workshop participants would be difficult. Large pharmaceutical companies might not be interested due to waiting games and the low priority for nanotech‐ nologies. Clinicians might not be interested, due to their limited involvement until now. It indeed proved difficult to attract participants from large pharmaceutical companies and, for that matter, biopharmaceutical companies, to attend the workshop on drug delivery - despite efforts by the co-organizing branche organizations. Nanotechnologies were not a high priority for potential participants and caution in discussing R&D developments were provided as important reasons for not attending the workshop. Attracting clinicians also proved to be difficult, albeit for different reasons. While some clinicians were interested in the phenomenon of nanotechnologies, but not able to attend due to busy schedules, others were sceptical about the value of nanotechnologies and not interested in participating in the workshop. These observations are relevant as they already give indications of possible difficulties in bringing

longer circulation time of drugs.

Selection and position of actors Big pharma as gatekeepers regarding development of new options.

and food sector.

Assessment of broader dynamics Linkages between drug delivery and imaging sector; between drug delivery

Focus on promises of targeting applications, but also on other promises such as

Long history of development and few products on the market yet. Nanotechnologies not high priority on drug delivery sectors' agenda.

Important to involve and link academia, industry and clinicians

pharmaceutical companies; perception of nanotechnology risks

Emerging consortia and platforms for drug delivery researchers and other actors interested in drug delivery (often linked to nanomedicine).

Attention to regulatory and clinical aspects, less on broader issues such as

Overall developments: reimbursement pressures; mergers and job cuts at large

Waiting games between actors in the value chain.

Uptake of notion of 'translational research'.

patient involvement, reliability and liability.

While eventually no clinicians or participants from large pharmaceutical companies attended, participants from different parts of the chain were present at the workshop, including some who had experiences with interactions with pharmaceutical companies and clinicians. Participants from knowledge institutes, suppliers of delivery systems, and a drug develop‐ ment firm were present. In addition, a firm involved with microsystem technologies and a

To prepare for the discussion and support participants thinking about current and future developments, three scenarios were crafted. One scenario explored two different (and

about co-ordination in the field regarding emerging NDDS.

**Table 2.** Summary of pre-engagement drug delivery workshop

**Pre-engagement requirements Findings**

512 Application of Nanotechnology in Drug Delivery

Understanding of dynamics in the

Actors' propensity to co-ordinate development and embedding of

domain

NDDS

governmental organization involved with nanotechnologies were present.

The third scenario explored attempts at stimulation and co-ordination from the demand-side. An alliance of patient organizations, knowledge institutes and firms is forged with the general aim of stimulating demand for cancer medicines with little side-effects. The alliance develops a broad research programme and actively involves itself in political circles and decision processes on the restructuration of the health care system and reimbursement policies. The broad focus on stimulating demand for reduction of side-effects of medicines attracts various alternative technology solutions. Only with help with the reference to cancer medicines, nanoenabled targeted drug delivery system remain on the agenda within the research programme which is eventually funded. First clinical evidence suggests that complexity of cancer requires different forms of drug delivery systems which may be commercially less attractive because of limited market volumes. Involved patient organizations are disappointed and press for applications fitting their specific diseases. The push of the alliance for medicines with less sideeffects then starts to lose its momentum. The emphasis on cancers as the major disease area now appears to be less effective to mobilize resources.

To inform the participants a preparatory document was distributed one week before the workshop. This document contained: (1) a program of the meeting; (2) a short introduction into and justification of the topic of the meeting; (3) a brief analysis of the current situation of development and embedding of nanotechnologies for drug delivery; (4) the presentation of scenarios; and (5) a list of identified dilemmas where strategic choices about development and societal embedding of nanotechnology-enabled drug delivery systems had to be made. The document aimed to create common ground for participants, and offer ideas for discussion. In particular the scenarios and dilemmas were offered as ways to think about future develop‐ ments and strategies. It was emphasized that the scenarios were controlled speculations [22], i.e. imagined developments but based on what was happening in the drug delivery sector already. Participants were invited to modify and add to the scenarios during the workshop.

particles in the body – which would suggest the existence of specific nanotechnology related

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This question regarding safety of nano drug delivery technologies prompted a participant, working for a company supplying drug delivery systems, to frame the question differently by asking about the status of knowledge and methodologies for assessing 'conventional' phar‐ maceutical materials. This participant considered questions regarding safety to be the respon‐ sibility of their customers and not a topic for his firm. However, by asking about evaluation criteria for their customers' products, his understanding of broader developments increased.

In that respect, this participant did consider broader developments rather than only customer-

*Delivery systems supplier: May I ask a simple question? We discussed that we cannot observe where nanoparticles are travelling to, but this is also unknown for pharmaceutical substances, molecules. Also*

*Knowledge institute 2: There is pre-clinical pharmacokinetics, tissue distribution; this should all be*

*Governmental organization: But that is not different for what needs to be done already for pharmaceutical*

*Delivery systems supplier: Hence, my question. If this is already being done for small molecules, why*

*Governmental organization: Because for non-nanoparticles, let's call them that way, for other chemical substances, not necessarily pharmaceutical compounds, already a number of patterns are known. [...]*

Even if questions concerning the unique character of nanotechnologies for drug delivery were unsolved, the link between general conceptualizations of the term nanotechnology and drug delivery was problematized. Participants from research institutes and a drug development firm pointed out that the associations of targeted drug delivery with the umbrella term 'nanotechnology' also, albeit incorrectly, implied connections with discussions of 'disadvan‐ tages or risks' linked to nanotechnologies in the public domain. According to these partici‐ pants, such associations could provide nuisances for nano drug delivery technologies. This type of reasoning shows that these enactors take broader aspects into account, yet in a way which resembles other patterns which have been called by Rip [14] as 'folk theories': taken for granted patterns, which have not systematically been checked. In this case, the expectation that nanotechnologies may suffer from the same public backlash as what happened to GMOs.

4 During my post-workshop interviews this participant expressed that understanding in this area helped the firm to assess their business plan forecasts as uncertainties in this area might slow down introductions of their customers'

*in these cases one doesn't analyze in detail whether particles travel to the liver, or to.*

challenges - or required more efforts during testing was unclear.

4

*done.*

*substances.*

supplier exchanges.

*Knowledge institute 2: Well, well*

*Delivery systems supplier: They do?*

*would this be problematic for nanoparticles?*

products, and therefore the participants' sales volume.

*The case of nanoparticles is becoming a totally different story for us.*

#### **4.2. Discussions during the workshop**

The workshop consisted of a half-day of intense discussions which took place in an informal atmosphere.3 While the workshop discussions covered a variety of themes, there was a strong focus on the clinical value of nanotechnology-enabled drug delivery technologies. Sectoral issues of co-ordination between disciplines and across positions in the chain emerged as the most important challenges to be overcome. They were recognized and were actually high‐ lighted by some participants in the workshops as being a key factor holding back embedding processes of nano drug delivery technologies. The lack of clinical evidence of (significant) therapeutical effectiveness was positioned as the reverse salient for furthering developments in the field. Strategies to stimulate and improve further developments in the field of nanoenabled drug delivery revolved around the challenge of demonstrating clinical value.

Interactions during the targeted drug delivery workshop are characterized as a series of exchanges on diagnosing the key challenges in furthering developments in the field of nanotechnologies and drug delivery, and on the best methods to cope with those challenges. While there was no explicit consensus on which strategies should be pursued in the future, the emphasis on problems of co-ordination and lack of clinical evidence effectively constituted a lock-in in the discussion. To show how participants in the workshops assessed current dynamics and anticipated future developments relevant for the commercialization of nanoenabled drug delivery systems I will report on salient items in the discussions.

#### *4.2.1. The unique character of nanotechnology and the pharmaceutical sector*

Puzzles about the unique character, if any, of nanotechnology engineered drug delivery technologies set the stage for a series of exchanges. The discussion was initiated by a participant wondering about specificities of the application of nanotechnologies and how these contrib‐ uted to reluctance in uptake and development of nanotechnology-enabled drug delivery technologies. A participant from a drug development company replied by pointing out uncertainties about the unknown safety profile of nanoparticles. Whether this meant that there was a lack of testing methodologies and knowledge about distribution and effects of nano‐

<sup>3</sup> The quotations in this chapter are anonymized, and used with permission of the participants. The quotations were translated into English by the author.

particles in the body – which would suggest the existence of specific nanotechnology related challenges - or required more efforts during testing was unclear.

This question regarding safety of nano drug delivery technologies prompted a participant, working for a company supplying drug delivery systems, to frame the question differently by asking about the status of knowledge and methodologies for assessing 'conventional' phar‐ maceutical materials. This participant considered questions regarding safety to be the respon‐ sibility of their customers and not a topic for his firm. However, by asking about evaluation criteria for their customers' products, his understanding of broader developments increased. 4 In that respect, this participant did consider broader developments rather than only customersupplier exchanges.

*Delivery systems supplier: May I ask a simple question? We discussed that we cannot observe where nanoparticles are travelling to, but this is also unknown for pharmaceutical substances, molecules. Also in these cases one doesn't analyze in detail whether particles travel to the liver, or to.*

*Knowledge institute 2: Well, well*

into and justification of the topic of the meeting; (3) a brief analysis of the current situation of development and embedding of nanotechnologies for drug delivery; (4) the presentation of scenarios; and (5) a list of identified dilemmas where strategic choices about development and societal embedding of nanotechnology-enabled drug delivery systems had to be made. The document aimed to create common ground for participants, and offer ideas for discussion. In particular the scenarios and dilemmas were offered as ways to think about future develop‐ ments and strategies. It was emphasized that the scenarios were controlled speculations [22], i.e. imagined developments but based on what was happening in the drug delivery sector already. Participants were invited to modify and add to the scenarios during the workshop.

The workshop consisted of a half-day of intense discussions which took place in an informal atmosphere.3 While the workshop discussions covered a variety of themes, there was a strong focus on the clinical value of nanotechnology-enabled drug delivery technologies. Sectoral issues of co-ordination between disciplines and across positions in the chain emerged as the most important challenges to be overcome. They were recognized and were actually high‐ lighted by some participants in the workshops as being a key factor holding back embedding processes of nano drug delivery technologies. The lack of clinical evidence of (significant) therapeutical effectiveness was positioned as the reverse salient for furthering developments in the field. Strategies to stimulate and improve further developments in the field of nano-

enabled drug delivery revolved around the challenge of demonstrating clinical value.

enabled drug delivery systems I will report on salient items in the discussions.

*4.2.1. The unique character of nanotechnology and the pharmaceutical sector*

Interactions during the targeted drug delivery workshop are characterized as a series of exchanges on diagnosing the key challenges in furthering developments in the field of nanotechnologies and drug delivery, and on the best methods to cope with those challenges. While there was no explicit consensus on which strategies should be pursued in the future, the emphasis on problems of co-ordination and lack of clinical evidence effectively constituted a lock-in in the discussion. To show how participants in the workshops assessed current dynamics and anticipated future developments relevant for the commercialization of nano-

Puzzles about the unique character, if any, of nanotechnology engineered drug delivery technologies set the stage for a series of exchanges. The discussion was initiated by a participant wondering about specificities of the application of nanotechnologies and how these contrib‐ uted to reluctance in uptake and development of nanotechnology-enabled drug delivery technologies. A participant from a drug development company replied by pointing out uncertainties about the unknown safety profile of nanoparticles. Whether this meant that there was a lack of testing methodologies and knowledge about distribution and effects of nano‐

3 The quotations in this chapter are anonymized, and used with permission of the participants. The quotations were

**4.2. Discussions during the workshop**

514 Application of Nanotechnology in Drug Delivery

translated into English by the author.

*Delivery systems supplier: They do?*

*Knowledge institute 2: There is pre-clinical pharmacokinetics, tissue distribution; this should all be done.*

*Governmental organization: But that is not different for what needs to be done already for pharmaceutical substances.*

*Delivery systems supplier: Hence, my question. If this is already being done for small molecules, why would this be problematic for nanoparticles?*

*Governmental organization: Because for non-nanoparticles, let's call them that way, for other chemical substances, not necessarily pharmaceutical compounds, already a number of patterns are known. [...] The case of nanoparticles is becoming a totally different story for us.*

Even if questions concerning the unique character of nanotechnologies for drug delivery were unsolved, the link between general conceptualizations of the term nanotechnology and drug delivery was problematized. Participants from research institutes and a drug development firm pointed out that the associations of targeted drug delivery with the umbrella term 'nanotechnology' also, albeit incorrectly, implied connections with discussions of 'disadvan‐ tages or risks' linked to nanotechnologies in the public domain. According to these partici‐ pants, such associations could provide nuisances for nano drug delivery technologies. This type of reasoning shows that these enactors take broader aspects into account, yet in a way which resembles other patterns which have been called by Rip [14] as 'folk theories': taken for granted patterns, which have not systematically been checked. In this case, the expectation that nanotechnologies may suffer from the same public backlash as what happened to GMOs.

<sup>4</sup> During my post-workshop interviews this participant expressed that understanding in this area helped the firm to assess their business plan forecasts as uncertainties in this area might slow down introductions of their customers' products, and therefore the participants' sales volume.

A series of interactions followed in which a participant from a governmental organization questioned this implicit pattern. This participant pointed out that specificities of the drug delivery sector would limit possible risks of nanotechnologies. Exposure to nanotechnologies through pharmaceutical therapies would be well controlled and registration procedures would check, among other things, toxicity. In addition, access to consumers – patients – would be regulated through intervention of clinicians. Furthermore, authorities had already consid‐ erable experience with delivery systems such as liposomes, suggesting that registration procedures should not pose particular difficulties. However, the participant acknowledged, patients might think differently about risks than experts do.

*industry is waiting for [..] but big pharmaceutical companies are not in-active altogether. On the one hand there is a development which forces them to pay attention to these type of products, eventually. Because there are increasingly less blockbusters. [..] Big pharmaceutical companies do have interest in*

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According to participants from research institutes, big pharmaceutical industries were reluctant. This led the participant from the governmental organization to probe into big pharma's considerations. While no participant from big pharma was present, participants replied by referring to big pharma's waiting strategy, which was considered to be independent of nanotechnologies. A participant from a drug development company pointed out that, among other commercial considerations, clinical proof established in Phase II studies was required to demonstrate the added value of a new pharmaceutical technology. The participant from the governmental organization challenged this claim. The participant probed whether clinical studies were really required in order to convince pharmaceutical companies to invest in nanotechnologies. This was confirmed by a number of participants and not questioned by

Focus on convincing large pharmaceutical companies by acquiring – hopefully – significant clinical data (for a specific drug – delivery systems – disease combination) was an important topic in the workshop. The consideration of evaluation criteria from pharmaceutical compa‐ nies (acting as future selectors of concepts generated by research institutes) by participants from research institutes and firms implies that these actors did take into account broader aspects. Still, the discussion was focused on pushing forward nanotechnologies (from the world of research). The overall strategy itself is predicated on the assumption that convincing firms and health insurers that clinical evidence is 'out there' and that expected benefits only need to be harvested – after which new drug delivery technologies will enter into the clinics.

One of the participants pointed out further sectoral dynamics. The participant argued that big pharma had a strong focus on blockbuster drugs and that novel nanotechnology enabled drug delivery technologies would not likely fall under that class of drugs. This then led to a series of interactions regarding structural features in the drug delivery sector constraining develop‐ ment of new pharmaceutical technologies in general. During this set of interactions one participant, who emphasized clinical proof, suggested that if the clinical value would be convincing, actors (which were left unspecified) could not dismiss these technologies. The emphasis on benefits, which would overcome all barriers, is a typical enactor perspective. But this was not left unchallenged. One participant remarked that patients then probably needed to take action as health insurers might be reluctant to pay for new (costly) therapies. Here, we see a typical selector argument, pointing out that benefits alone might not be sufficient, as

issues of costs were known to limit introduction of new pharmaceutical therapies.

Participants raised further points to open up the discussion, thereby moving away from the lock-in on clinical value of drug delivery technologies, which was pushed by a number of participants. One of the participants challenged the idea of initiating technology development

*these [nano drug delivery] type of systems. Watch it carefully*.

This type of reasoning resembles a typical enactor perspective.

trajectories from a disease oriented point of view.

others.

The point about regulatory expertise was contested by one of the participants who had experience with regulatory authorities, puzzling over whether existing evaluations were sufficient – even for liposomal formulations. The participant speculated that more knowledge about risks of nanotechnologies might lead to re-evaluating existing registration procedures. This prompted a reflective comment from the participant of the governmental organization, noting that there were tendencies in society to reduce and solve all uncertainties and problems linked to nanomaterials. While such an objective might be laudable, the participant warned that one should not increase risk assessment criteria for nanotechnologies beyond what was presently accepted.

#### *4.2.2. Challenges in co-ordination across the innovation chain*

During the discussion the point was made that the development of linkages between research on drug delivery materials and specific diseases was difficult. A participant from a knowledge institute suggested that research programmes should stimulate the improvement of interfaces within a chain of activities involved in developing these linkages. At the same time, this participant observed that developing linkages would not be straightforward, for different reasons.

*Knowledge institute 1: There are also groups that only focus on researching their own chemical entities and do not develop them further. While, clearly, further development of these substances should be considered. In which area do you want to have an application? Then you also need a partner to do this. We, as material developers, are all confronted with the problem that we have difficulties in reaching those people, particularly the industrial actors which are interested in these materials.*

According to a participant from another knowledge institute, the difficulty in bringing the field of nanotechnology enabled targeted drug delivery further was rooted in the lack of clinical evidence. This would make it difficult for researchers and drug delivery firms to link up with large pharmaceutical companies. Later, the participant commented that big pharmaceutical companies were to some extent dependent on these new technologies. So, we see here a waiting game at work, considering that researchers and firms are to some extent dependent on large pharmaceutical companies for funding and further exploitation of nanotechnology enabled delivery systems.

*Knowledge institute 2: There is still too little on the market that convinces large companies to put effort in this area. There is very little data on the clinical benefits. Real, concrete proof. And that is what the* *industry is waiting for [..] but big pharmaceutical companies are not in-active altogether. On the one hand there is a development which forces them to pay attention to these type of products, eventually. Because there are increasingly less blockbusters. [..] Big pharmaceutical companies do have interest in these [nano drug delivery] type of systems. Watch it carefully*.

A series of interactions followed in which a participant from a governmental organization questioned this implicit pattern. This participant pointed out that specificities of the drug delivery sector would limit possible risks of nanotechnologies. Exposure to nanotechnologies through pharmaceutical therapies would be well controlled and registration procedures would check, among other things, toxicity. In addition, access to consumers – patients – would be regulated through intervention of clinicians. Furthermore, authorities had already consid‐ erable experience with delivery systems such as liposomes, suggesting that registration procedures should not pose particular difficulties. However, the participant acknowledged,

The point about regulatory expertise was contested by one of the participants who had experience with regulatory authorities, puzzling over whether existing evaluations were sufficient – even for liposomal formulations. The participant speculated that more knowledge about risks of nanotechnologies might lead to re-evaluating existing registration procedures. This prompted a reflective comment from the participant of the governmental organization, noting that there were tendencies in society to reduce and solve all uncertainties and problems linked to nanomaterials. While such an objective might be laudable, the participant warned that one should not increase risk assessment criteria for nanotechnologies beyond what was

During the discussion the point was made that the development of linkages between research on drug delivery materials and specific diseases was difficult. A participant from a knowledge institute suggested that research programmes should stimulate the improvement of interfaces within a chain of activities involved in developing these linkages. At the same time, this participant observed that developing linkages would not be straightforward, for different

*Knowledge institute 1: There are also groups that only focus on researching their own chemical entities and do not develop them further. While, clearly, further development of these substances should be considered. In which area do you want to have an application? Then you also need a partner to do this. We, as material developers, are all confronted with the problem that we have difficulties in reaching*

According to a participant from another knowledge institute, the difficulty in bringing the field of nanotechnology enabled targeted drug delivery further was rooted in the lack of clinical evidence. This would make it difficult for researchers and drug delivery firms to link up with large pharmaceutical companies. Later, the participant commented that big pharmaceutical companies were to some extent dependent on these new technologies. So, we see here a waiting game at work, considering that researchers and firms are to some extent dependent on large pharmaceutical companies for funding and further exploitation of nanotechnology enabled

*Knowledge institute 2: There is still too little on the market that convinces large companies to put effort in this area. There is very little data on the clinical benefits. Real, concrete proof. And that is what the*

*those people, particularly the industrial actors which are interested in these materials.*

patients might think differently about risks than experts do.

*4.2.2. Challenges in co-ordination across the innovation chain*

presently accepted.

516 Application of Nanotechnology in Drug Delivery

reasons.

delivery systems.

According to participants from research institutes, big pharmaceutical industries were reluctant. This led the participant from the governmental organization to probe into big pharma's considerations. While no participant from big pharma was present, participants replied by referring to big pharma's waiting strategy, which was considered to be independent of nanotechnologies. A participant from a drug development company pointed out that, among other commercial considerations, clinical proof established in Phase II studies was required to demonstrate the added value of a new pharmaceutical technology. The participant from the governmental organization challenged this claim. The participant probed whether clinical studies were really required in order to convince pharmaceutical companies to invest in nanotechnologies. This was confirmed by a number of participants and not questioned by others.

Focus on convincing large pharmaceutical companies by acquiring – hopefully – significant clinical data (for a specific drug – delivery systems – disease combination) was an important topic in the workshop. The consideration of evaluation criteria from pharmaceutical compa‐ nies (acting as future selectors of concepts generated by research institutes) by participants from research institutes and firms implies that these actors did take into account broader aspects. Still, the discussion was focused on pushing forward nanotechnologies (from the world of research). The overall strategy itself is predicated on the assumption that convincing firms and health insurers that clinical evidence is 'out there' and that expected benefits only need to be harvested – after which new drug delivery technologies will enter into the clinics. This type of reasoning resembles a typical enactor perspective.

One of the participants pointed out further sectoral dynamics. The participant argued that big pharma had a strong focus on blockbuster drugs and that novel nanotechnology enabled drug delivery technologies would not likely fall under that class of drugs. This then led to a series of interactions regarding structural features in the drug delivery sector constraining develop‐ ment of new pharmaceutical technologies in general. During this set of interactions one participant, who emphasized clinical proof, suggested that if the clinical value would be convincing, actors (which were left unspecified) could not dismiss these technologies. The emphasis on benefits, which would overcome all barriers, is a typical enactor perspective. But this was not left unchallenged. One participant remarked that patients then probably needed to take action as health insurers might be reluctant to pay for new (costly) therapies. Here, we see a typical selector argument, pointing out that benefits alone might not be sufficient, as issues of costs were known to limit introduction of new pharmaceutical therapies.

Participants raised further points to open up the discussion, thereby moving away from the lock-in on clinical value of drug delivery technologies, which was pushed by a number of participants. One of the participants challenged the idea of initiating technology development trajectories from a disease oriented point of view.

*Knowledge institute 3: I would like to react to your comment to take diseases as a starting point. There are of course many material research groups which start to think from their technology. [...] If you assert that one needs to start to think from the clinical picture, this means that you actually need to involve all groups in that discussion. [...] For each disease there are then several delivery systems. Whereas one could also say that one should start thinking from delivery systems and whether they are toxic or not.*

*Knowledge institute 1: There is also an opportunity in which one could make up for some costs. There are of course many pharmaceuticals which in the end have not made it due to side-effects. Targeted delivery offers an opportunity to avoid such toxic side-effects. The therapeutic effect will probably already have been demonstrated very clearly, but in the end they have not made it due to the side-effects. In that respect one may skip some developments, or at least short-cut them and focus on whether one can reduce*

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*Knowledge institute 2: Yes, yes, but you can also evoke them [side-effects] via targeting. That automat‐*

*Knowledge institute 3: Big pharmaceutical companies have many pharmaceuticals on the shelves [which*

*Knowledge institute 2: We have already tried that many times in the past. [...] And eventually it works, pre-clinically, and they [big pharmaceutical companies] do not do anything with it. Because it doesn't fit with their block buster model eventually, and it is too laborious, costs too much money and finally they pull out. We had spoken already with a number of big pharmaceutical firms in the past about creating a better life for interesting pharmaceuticals, problem medicine. And, that is, … well, yes, big*

During the discussion of strategies to further the field, also the question of mobilizing resources for such strategies was put forward for consideration. Toward the end of the meeting the moderator pointed to one of the scenarios in which patient foundations and organizations were involved and asked whether that would be a feasible option. Patient organizations can be involved for financial but also symbolic (moral) support. Participants from research institutes and the governmental organization were hesitant and argued that it might be too early to involve them for funding and moral support. Too-high expectations based on too little evidence and uncertainties over risks were mentioned as reasons (without making explicit the expected effects). Between the lines, the analyst can see a folk theory of a hype-disappointment

Interestingly, one of the participants from a firm not directly involved with drug delivery technologies responded to this discussion by pointing out that little involvement of patient organizations might induce a pattern reminiscent of the biotech discussions. A pattern, argued the participant, in which little information by enactors of new technologies is distributed, leaving civil society organizations to guess what is happening and perhaps leading to a rejection of new technologies. This was acknowledged by one of the participants from a research institute as something for which an answer should be developed, but not as something directly important for the question of furthering the field. This participant considered this theme as off topic and (again) emphasized the importance of clinical evaluation of new delivery

By convening participants at various positions in the chain and facilitating mutual under‐ standing of each other's positions and perspectives, the workshop supported the participants

*Governmental organization: Yes, [...] one should also have a look at the deleted products.*

*ically appears, safety, you can not eliminate that, because through linking…*

*these side-effects through targeting.*

*pharma does not think that way.*

cycle at work.

technologies.

*cannot be used due to drug delivery problems].*

*[...]*

*Knowledge institute 2: Yes, but eventually we develop, we produce [...] not things that are safe. No, we produce things that have to work effectively and which have to help patients [...] Look, it is a bit like, disease searches for a device, or device searches for a disease.*

### *Microtechnology firm: It is an interaction.*

*Knowledge institute 2: It is an interaction. And actually I am also in favor of broad academic research. But, if one takes the step to, let's call it, valorization, then one needs to make a small value chain and this should be done by spin-offs.*

*[..]*

*Knowledge institute 1: You need them both, of course. You need to have a lot of knowledge about particles in order to know how and for what you can use them. [..] So, there is a disease and there is a material, and these should be brought together. How would you like to improve this? Then one would say, for these connections, these points, there should be programs that support them.*

The conclusion that interfaces between actors needed to be improved can be interpreted as a call for translational research, although the term itself was not employed. The conclusion shows a non-typical enactor perspective; enactment of new technologies is guided by a diagnosis of what happens at the level of a sector and what should be improved upon.

#### *4.2.3. Anticipatory strategies: next steps in mobilizing R&D funds and research*

The relatively focused discussion created time and space for discussion and articulation of strategies. Discussions focused on the question of how to further develop nanotechnologies in the drug delivery sector. Overcoming what was seen as the reverse salient in the overall development, the lack of clinical evidence, was a central theme in that part of the discussion. Participants explored possible strategies of co-ordinating developments in the sector, includ‐ ing the creation of a nano drug delivery exemplar which – if successful – might convince the field of drug delivery of the value of the application of nanotechnologies. Toward the end of the workshop participants expressed interest and enthusiasm in adopting the discussed strategy in order to try to actually implement them

Other strategies were explored well. One is particularly interesting as it appealed to the promise of reducing undesirable side-effects. In the interactions that followed, not only researchers, enactors, of drug delivery technologies were articulating this strategy, but also the participant of the governmental organization. One of the participants rebutted this strategy by referring to negative experiences with large pharmaceutical companies. According to this participant, the strategy of re-evaluating problematic drugs did not fit with big pharma's practices. By providing an account of those experiences, the participant also provided further insights into the world of large pharmaceutical companies:

*Knowledge institute 1: There is also an opportunity in which one could make up for some costs. There are of course many pharmaceuticals which in the end have not made it due to side-effects. Targeted delivery offers an opportunity to avoid such toxic side-effects. The therapeutic effect will probably already have been demonstrated very clearly, but in the end they have not made it due to the side-effects. In that respect one may skip some developments, or at least short-cut them and focus on whether one can reduce these side-effects through targeting.*

*Knowledge institute 2: Yes, yes, but you can also evoke them [side-effects] via targeting. That automat‐ ically appears, safety, you can not eliminate that, because through linking…*

*[...]*

*Knowledge institute 3: I would like to react to your comment to take diseases as a starting point. There are of course many material research groups which start to think from their technology. [...] If you assert that one needs to start to think from the clinical picture, this means that you actually need to involve all groups in that discussion. [...] For each disease there are then several delivery systems. Whereas one could also say that one should start thinking from delivery systems and whether they are toxic or not. Knowledge institute 2: Yes, but eventually we develop, we produce [...] not things that are safe. No, we produce things that have to work effectively and which have to help patients [...] Look, it is a bit like,*

*Knowledge institute 2: It is an interaction. And actually I am also in favor of broad academic research. But, if one takes the step to, let's call it, valorization, then one needs to make a small value chain and*

*Knowledge institute 1: You need them both, of course. You need to have a lot of knowledge about particles in order to know how and for what you can use them. [..] So, there is a disease and there is a material, and these should be brought together. How would you like to improve this? Then one would say, for*

The conclusion that interfaces between actors needed to be improved can be interpreted as a call for translational research, although the term itself was not employed. The conclusion shows a non-typical enactor perspective; enactment of new technologies is guided by a diagnosis of what happens at the level of a sector and what should be improved upon.

The relatively focused discussion created time and space for discussion and articulation of strategies. Discussions focused on the question of how to further develop nanotechnologies in the drug delivery sector. Overcoming what was seen as the reverse salient in the overall development, the lack of clinical evidence, was a central theme in that part of the discussion. Participants explored possible strategies of co-ordinating developments in the sector, includ‐ ing the creation of a nano drug delivery exemplar which – if successful – might convince the field of drug delivery of the value of the application of nanotechnologies. Toward the end of the workshop participants expressed interest and enthusiasm in adopting the discussed

Other strategies were explored well. One is particularly interesting as it appealed to the promise of reducing undesirable side-effects. In the interactions that followed, not only researchers, enactors, of drug delivery technologies were articulating this strategy, but also the participant of the governmental organization. One of the participants rebutted this strategy by referring to negative experiences with large pharmaceutical companies. According to this participant, the strategy of re-evaluating problematic drugs did not fit with big pharma's practices. By providing an account of those experiences, the participant also provided further

*these connections, these points, there should be programs that support them.*

*4.2.3. Anticipatory strategies: next steps in mobilizing R&D funds and research*

strategy in order to try to actually implement them

insights into the world of large pharmaceutical companies:

*disease searches for a device, or device searches for a disease.*

*Microtechnology firm: It is an interaction.*

518 Application of Nanotechnology in Drug Delivery

*this should be done by spin-offs.*

*[..]*

*Knowledge institute 3: Big pharmaceutical companies have many pharmaceuticals on the shelves [which cannot be used due to drug delivery problems].*

*Governmental organization: Yes, [...] one should also have a look at the deleted products.*

*Knowledge institute 2: We have already tried that many times in the past. [...] And eventually it works, pre-clinically, and they [big pharmaceutical companies] do not do anything with it. Because it doesn't fit with their block buster model eventually, and it is too laborious, costs too much money and finally they pull out. We had spoken already with a number of big pharmaceutical firms in the past about creating a better life for interesting pharmaceuticals, problem medicine. And, that is, … well, yes, big pharma does not think that way.*

During the discussion of strategies to further the field, also the question of mobilizing resources for such strategies was put forward for consideration. Toward the end of the meeting the moderator pointed to one of the scenarios in which patient foundations and organizations were involved and asked whether that would be a feasible option. Patient organizations can be involved for financial but also symbolic (moral) support. Participants from research institutes and the governmental organization were hesitant and argued that it might be too early to involve them for funding and moral support. Too-high expectations based on too little evidence and uncertainties over risks were mentioned as reasons (without making explicit the expected effects). Between the lines, the analyst can see a folk theory of a hype-disappointment cycle at work.

Interestingly, one of the participants from a firm not directly involved with drug delivery technologies responded to this discussion by pointing out that little involvement of patient organizations might induce a pattern reminiscent of the biotech discussions. A pattern, argued the participant, in which little information by enactors of new technologies is distributed, leaving civil society organizations to guess what is happening and perhaps leading to a rejection of new technologies. This was acknowledged by one of the participants from a research institute as something for which an answer should be developed, but not as something directly important for the question of furthering the field. This participant considered this theme as off topic and (again) emphasized the importance of clinical evaluation of new delivery technologies.

By convening participants at various positions in the chain and facilitating mutual under‐ standing of each other's positions and perspectives, the workshop supported the participants in getting a richer understanding of what happens at the level of the drug delivery sector. This was acknowledged by one of the participants after the workshop who remarked that the meeting discussed the big challenges at the level of the domain which was usually not done as people tend to be preoccupied with their day-to-day affairs.

By organizing an interactive discussion involving participants at different positions in the value chain, supported by well-prepared scenarios, analysts or practitioners adopting CTA methodologies can support articulation of anticipatory strategies and decision making. Whether the insights gained during such events actually make a difference is more difficult to determine, among others because this depends on how much opportunities and room to maneuver participants have after the workshop. The workshops will however contribute to an emerging shared understanding of dynamics and issues which cannot be easily ignored by the individual participants. This will be different than before the workshop and in that sense the workshop will already have effects on how actors will anticipate market introduction of

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This work is supported by NanoNextNL, a micro and nanotechnology consortium of the

Department of Science, Technology & Policy Studies, School of Management and Gover‐

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**Acknowledgements**

**Author details**

Haico Te Kulve

**References**

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