pharmacologists
Figure 1: A microbial art painting by Alexander Fleming of a woman feeding her baby. Fleming placed microbes with diᤀ鸄erent pigments in an agar dish, and timed his inoculation so that the species of bacterium matured at the same time . (Source: The Alexander Fleming Laboratory Museum, via Smithsonian )
Samuel James Credgington
Student number: 11124482
MSc Medical Anthropology and Sociology Universiteit van Amsterdam
Amsterdam, August 2016
Supervision: dhr. prof. dr. J.D.M van der Geest - Emeritus Professor of Medical Anthropology at the University of Amsterdam
Second Reader: dr. R.P.M. Gerrits - Assistant Professor in the Department of Anthropology and Sociology and Co-director of the MAS, University of Amsterdam
Table of Contents
Acknowledgements 3 Preface 4 I - Introduction 5
The ‘early life of the pharmaceutical’ 6
Rationale 8
II - Methodology 9
Limitations 11
III - An ethnography of the phase I trial 13
The centre 13
The phase I trial 14
IV - How investors and pharmacologists relate to the compound 22
An attachment to the compound 22
How attachment becomes possible 24
The importance of values 26
Killing the compound 27
Removing the subjective 29
Following the compound 31
Value (in)coherence 34
V - Theoretical analysis 41
A problematic dichotomy 41
What about the pharmacologists? 44
The value-free ideal 46
Objectivity as construction 46 Detached objectivity 48 VI - Conclusions 53 Bibliography 56 Appendices 59
Appendix A - List of acronyms 59
Appendix B - The Rennes incident 60
Acknowledgements
I would like to thank Marieke and Rik, whose invitation for dinner, and patience with my endless questioning about the place where they worked, led to this ethnographic adventure. Appreciation is also
due to Adam and Martijn, whose curiosity about anthropology made this ᤀ┄eld research possible, and to Roman, for his brilliant companionship on the daily ride to work. Finally, I would like to thank all of the
colleagues at the centre, for their interest and honesty throughout the duration of my stay. It is my deepest regret that I cannot include all of the thoughts and opinions I was so fortunate to hear.
Preface
This thesis came about following a seven week internship at a clinical research organisation that specialises in early phase drug development. Upon scheduling a meeting with the Chief Executive Oᤀ搆cer at the centre, we sat over lunch, and I began to introduce my ambition to conduct some ethnographic research about the phase I trial, despite the fact I do not have a background in clinical pharmacology. After explaining what anthropology is, and what its typical methods entail, I made a slightly fumbling statement that “I’d like to show the human side of the pharmaceutical industry” . The CEO, who is a friendly and easygoing fellow (although I cannot say I was fully aware of that at the time), tilted his head and responded, “Are you trying to imply that we are not human?”.
I went on to explain that my frustrations were (and remain) founded upon a whole host of criticisms about the pharmaceutical industry at large (within social science and beyond), that bypass the many voices of professionals within the sector altogether. Thankfully, such a faux pas was laughed oᤀ鸄 soon after, and a fruitful conversation ensued about my curiosity in pharmacology, and desire to write about a ᤀ┄eld that has for the most part been reluctant to open its doors to social scientists.
An internship was arranged on the premise that I would interview personnel around the building upon scheduled appointments, and would contribute to a case study about the centre that explored the daily working lives of various professionals who occupy it. Looking back, I believe my initial apprehension to have arisen out of a fear that my presence would be an inconvenient interruption of the scientists’ valuable time. As I increasingly got used to my surroundings, it was evident that this was not the case, and that the intrigue was mutual. The colleagues at the centre were patient, open minded and willing to help my capturing of their (professional) point of view, which I hope in a small sense this thesis has achieved.
Chapter I Introduction
This thesis is an ethnographic investigation into the daily (working) lives of 21 clinical pharmacologists and their colleagues, situated at a clinical research organisation in the Netherlands. The major ᤀ┄nding is that a ‘social life of medicines’ (Whyte et al 2002: 13), which has been documented extensively
throughout patient populations worldwide, extends to this particular scientiᤀ┄c culture within the
landscape of early stage drug development. In line with following the ‘trajectory’ (Gaudillière 2005) or ‘life course’ (Van der Geest et al 2011) of medicines, the prior objective of this research was to determine if a relationship exists between the pharmacologists and the compounds that they routinely test, sometimes approve, yet most often reject after the phase I trial.
The short answer to this question is that the pharmaceutical does possess a life of it’s own during early stage clinical studies. Following seven weeks of ethnographic research, it became evident that several investors of a potential medication (individuals that are aᤀ┄lliated with biotech startups and 1
pharmaceutical companies), often develop a personal attachment to the compound that is inᤀ┄uenced by a ᤀ┄nancial and emotional investment. The consequence of such an attachment is a tendency for
irrational behaviours, such as rejecting phase I clinical data (much to the bemusement of 2
pharmacological professionals), excessive spending on further trials in desperation for positive results, an albeit rare temptation to encourage data manipulation and fraud, and on a semiotic level - the frequent comparison of the compound to the ‘baby' of the investor. In a climate of ruthless commerce and market driven decision making, the ‘life’ of the pharmaceutical is incredibly important to investors, with signiᤀ┄cantly large sums of money and sometimes personal careers at stake. In other words, the future of the company is inextricably tied to the future of the compound. As well as this, before the compound arrives at the phase I trial, it will have undergone years of experimental states on the lab table, taking a considerable ᤀ┄nancial and personal toll on the investor.
Crucially, pharmacologists do not share such an attachment, and oppositely distance themselves from any personal involvement, as their professional duties require a commitment to scientiᤀ┄c objectivity and rationality. That is however not to say that for these individuals the pharmaceutical does not possesses a life of it’s own. Rather that the ‘life’ of the compound is bound with hard, scientiᤀ┄c evidence that proves safety and early signs of eᤀ搆cacy during the liminal period of the clinical trial. Without such evidence, the compound is either to be killed, or alternatively if evidence is forthcoming, the object leaves the building
1 By ‘investor’, this paper throughout refers to individuals or groups of individuals representing a biotech startup or
pharmaceutical sponsor, who by virtue of their professional position, have a ᤀ┄nancial or personal stake in the compound itself.
2 The use of the word irrational is used to denote scientiᤀ┄c irrationality, that is behaviour which deᤀ┄es widely
to pursue the next stage of the pharmaceutical life course. Upon escaping the institute and the inᤀ┄uence of the pharmacologist, the scope for a long term involvement with the compound that is experienced by investors, is not shared. It is this long termism which evokes the subjective, emotional kind of
attachment this paper documents and seeks to explain.
In correspondence with Bruno Latour’s inᤀ┄uential studies (1979), this paper demonstrates how the 3
‘social’ and ‘technical’ are always interlocuting throughout scientiᤀ┄c research, yet are distinguished 4
carefully by scientists themselves, to uphold the integrity of methodological research. Integrally,
pharmacologists’ professionalism inspires an unbiased and unrelenting endeavour to know every minute detail about a potential compound with respect to its safety and early signs of eᤀ搆cacy. On the other hand, the investor (whose aᤀ搆nity to the compound is substantial), insists to be informed of every aspect of the clinical trial to ensure their considerable ᤀ┄nancial and personal investment is well returned. If the role of the pharmacologist and the investor is played out accordingly, and remains balanced, the phase I trial yields accurate and reliable results that the investor can either take forward into further drug
development, or in most cases, go back to the drawing board(room), to make an executive decision on the future of the compound. As is explored in depth, the predominant outcome is for the compound to be ‘killed’, which indicates that a social life exists in the form of a collective anthropomorphosis of the pharmaceutical as an object, and that the hostile journey of drug development, is indeed it’s life course.
The ‘early life of the pharmaceutical’
This thesis is then an exploration of the point of view that clinical pharmacologists hold about the
potential medications they test, to extend our understandings of the social lives of the medicines to early stages of drug development, in order to discover what the ‘early life of the pharmaceutical’ is, and what it entails. To those not familiar with the social lives of medicines, such a concept may appear rather odd. The crux of the endeavour is (in correspondence with Appadurai’s thesis ), to trace how medicines travel 5
through diᤀ鸄erent contexts, and to decipher values and meanings attributed to them. It is such interpretations made by humans beings, that allows the pharmaceutical (or formulation) to develop a (metaphorical) life of it’s own through various stages of the medicines’ trajectory, which includes (yet is not limited to):
3 This thesis is primarily in correspondence with the ᤀ┄rst chapter of Latour and Woolgar’s “Laboratory Life” (1979) to
the extent it explores features of scientiᤀ┄c practice from an anthropological ‘outsider’ perspective. As discussed in the conclusion, I do however take issue with the method of “scientiᤀ┄c realism” that Latour and Woolgar later pursue.
4 It is worth mentioning that this distinction between the social and the technical is useful in as far as it demonstrates
they are mutually constitutive throughout scientiᤀ┄c practice. What exactly is meant by these two terms remains problematic. This thesis utilises the terms to guide an understanding of the opposition between personal bias and objective neutrality, which chapter V discusses at length.
5 When ‘Appadurai’s thesis’ is mentioned, I refer to Appadurai, A. 1988. The Social Life of Things: commodities in
...production to marketing, their prescription, their distribution through intertwined formal and informal channels, their deaths through one form or another form of consumption, and ࿌nally their lives after death in the form of e႐cacy in modifying bodies (Whyte et al 2002: 14)
Over the past twenty years, ethnographic works have discovered a spectrum of localised
‘reinterpretations’ about medicines from within the most diverse of socio-cultural worlds (Hardon 1994, Whyte 1992, Han 2006, Lakoᤀ鸄 2006, Applbaum 2006, Das and Das 2006, Baxerres 2011). Crucially, these contributions have eᤀ鸄ectively grasped how pharmaceuticals “circulate in diᤀ鸄erent regimes of value in space and time” (Appadurai 1986: 4), and are “reinterpreted into local concepts and may thus turn into diᤀ鸄erent objects” (Bledsoe & Goubaud 1988: 253) by the patients who in one way or another consume them.
What is of real concern for anthropologists who have documented these localised reinterpretations, is a chasm of knowledge and information that distances the pharmaceutical industry from everyday lives of people. Das and Das epitomise this “informational asymmetry” (Ravelli 2011: 246) most poignantly by reminding us that; “ Patients are trying to learn language and world together but are repeatedly thwarted in their quest to understand the real” (Das and Das 2006: 195). Signiᤀ┄cant issues to public health such as side eᤀ鸄ects (Etkin 1992), overprescription (Busᤀ┄eld 2006), and drug safety problems (Fontanarosa et al 2004, Abraham & Davis 2005: 890) are often not held accountable by pharmaceutical companies, which envelopes the industry in a veil of secrecy which in turn for patient populations, breeds skepticism and mistrust (Hernandez 2015: 26). Without a prior intelligibility of a particular drug, a set of beliefs are constructed upon ontological experience of the medicine throughout “local moral worlds” (Kleinmann 1995: 17), which is then embedded into an individual, group or society’s value system.
This is in stark contrast to the in-depth understandings surrounding the pharmaceutical within the industry itself, where a set of “specialised knowledges” (Foucault 1977: 4) become deeply embedded within institutional spaces (e.g laboratories, hospital corridors and pharmaceutical conferences). These arenas have typically “closed their doors to social scientists” (Whyte et al 2002: 136), as well as to the general public, meaning ultimately that people are sealed oᤀ鸄 from sectors of biomedical expertise - and without a suᤀ搆cient mapping of the social life of the pharmaceutical during its beginnings as a potential medication, we are left incapable of formulating what beliefs and values exist in realms of drug
development, and how they may be warped along the trajectory of the pharmaceutical, before entering people's bodies and everyday lives.
Rationale
This thesis attempts to grasp the point of view of pharmacologists in relation to the experimental
compounds they test for the reason that by doing so, the perceptual shift (about medications) from areas of clinical pharmacology to patient populations can be identiᤀ┄ed, and better engaged with in the future. It is true that we already understand how “ the identity and properties of atoms and molecules are
transformed through their changing associations” (Barry 2005: 52), yet by having for the most part only observed the latter stages of the drug development process, a detailed mapping of how such
associations have changed has not been thoroughly explored. That being said, a few notable works have surfaced over the past two decades on early stages of the pharmaceutical life course which have set in motion this exploration. Emily Martin for instance explores how employees of pharmaceutical companies ᤀ┄nd meaning to their daily work amidst the “ growing public viliᤀ┄cation of the industry as rapacious and proᤀ┄t hungry” (2006: 157). Whilst Oldani (2004) and Ravelli (2011) focus upon how drug sales
representatives engage in a set of power and knowledge relations with prescribing physicians upon the (unequal) exchange of expertise about the pharmaceuticals they sell. The key commonality between these works that inspire this thesis, is an eᤀ鸄ort to locate beliefs, meanings and values held by actors within the pharmaceutical industry, without looking to criticise (or justify criticisms of) the sector, yet instead to grasp a point of view that emanates from a particular place and time.
The merit for being able to do so is that systemic problems within the industry that are i ntertwined with the pharmaceutical as it travels its life course such as inaᤀ鸄ordable drug prices, the
academic-pharmaceutical complex, ghost authorship, data manipulation, and wider ethics surrounding medical practice (Ghaemi 2013: 223), can be located via ethnographic studies that detail experience on a micro-scale. The signiᤀ┄cance of such an endeavour lies with the straightforward rationale that “In order to improve conditions of access to and use of medicine we need to understand the underlying processes that lead to these problems” (Van der Geest 2011: 9).
Of course, there are also the clinical pharmacologists themselves, who are groups of individuals that dedicate their professional life to the gatekeeping of future medications, yet are regularly painted with the same brush as the rest of the pharmaceutical industry. This is an opportunity for the voices of these professionals to take centre stage, which may pave the way for similar studies that capture daily scientiᤀ┄c processes which undisputedly contribute to the health and wellbeing of many populations, yet are simultaneously hardly understood by the patients within them.
Chapter II Methodology
The materials that provide the basis of discussion in this paper were accumulated during seven weeks of ethnographic research between April and June, 2016. The site of research was determined following an interview with the Chief Executive Oᤀ搆cer of the institute, who granted permission to hold interviews and focus group discussions with various professionals at the centre . Access was also granted to participate 6
in weekly meetings with the CardioVascular (CVS) and Central Nervous System (CNS) groups, fortnightly Scientiᤀ┄c Advisory Board meetings (SAB), and on one occasion, a meeting between a sponsor and the centre.
In terms of the research timeline, the ᤀ┄rst three weeks of the research were dedicated to exploring the building, and holding focus group discussions with each and every subpopulation of it. These groups included; recruitment, screening, administration, clinical trial assistants, human resources, business development, nurses, data management, ᤀ┄nance and statisticians. Each focus group discussion lasted approximately an hour in a meeting room or the canteen, and set about discovering various roles and responsibilities within the centre, in order to map out the phase I trial, which is undertaken in chapter one. These focus group discussions crucially facilitated a familiarisation with pharmacological
processes, technicalities and terminologies. Furthermore, they oᤀ鸄ered an in-depth, personal insight into how various individuals that liven the building conceptualise, critique and give meaning to their everyday practices. The questions asked in these discussions were semi structured, and focussed loosely upon what instigated the individual's interest in clinical pharmacology, their respective career trajectory, everyday experiences conducting the clinical trial, as well as perspectives on scientiᤀ┄c regulations and the drug development process. What became immediately clear during these two weeks was that although this thesis is primarily concerned with the point of view of the pharmacologist, the clinical trial is a collective enterprise that is reliant on various individuals’ expertise at diᤀ鸄erent stages of the process, which is detailed throughout the next chapter.
The fourth and ᤀ┄fth week of the research period were dedicated to interviewing twelve research physicians and clinical scientists at the centre, who are all training to be registered pharmacologists, whilst also obtaining a PHD. Similar to the focus group discussions, the interviews lasted an hour and followed a similar structure, yet were more detailed and technical. For instance, career trajectories were talked about more extensively to deduce why a career in the hospital or laboratory were not fulᤀ┄lling, and why the clinical trial and pharmacology had such an appeal. On a technical level, the questions were more orientated toward personal interest in the clinical trial, the scientiᤀ┄c and medical expertise that shapes pharmacology, and the compound itself. Generally, the interviews were semi structured, keeping
6 Access was attained in conjunction a two month internship as a qualitative researcher, whereby I also contributed
to four guiding themes - career trajectories, experiences of the clinical trial (and working with pharmaceutical sponsors), outward perspectives on the drug development process, and a recent incident in Rennes that claimed the life of one healthy volunteer and left ᤀ┄ve others with serious brain damage following a routine phase I clinical study. The sixth week involved interviews with senior clinical scientists, who are a bridge between the PHD students and the more experienced research directors. Interviews were almost of an identical format, although experiences and anecdotes were more detailed considering that these individuals have been pharmacologists and worked at the centre, for a longer period of time.
In the ᤀ┄nal week, the research directors were interviewed at the centre, which typically lasted about ninety minutes. These individuals are in a sense the ᤀ┄ve pillars of the organisation, with two of which being present since the inception of the institute. These interviews were particularly in depth with respect to the historical insight about the centre and the drug development process, and despite their
established positions at the centre, all spoke freely and critically about their own practices.
During the entirety of the research process, various meetings were attended to gain insight into the logistical workings of the organisation. Twice a week meetings held by the CVS (cardiovascular) and CNS (central nervous system) research groups were participated in. These meetings lasted an hour and became quite ritualistic in the sense that every trial at the centre was discussed brieᤀ┄y to monitor progress. Action items, incident reports, milestones, database locks, manuscripts and other business were attended to in an eᤀ搆cient manner. Such meetings greatly contributed to a better understanding of the overall process of the phase I trial, via an introduction to scientiᤀ┄c terms and methodologies, which provided insight into how pharmacologists talked about their practices, the clinical trial, sponsors, and the compound itself. On two occasions, scientiᤀ┄c advisory board (SAB) meetings were also attended. These meetings involve a gathering of the pharmacologists in an auditorium whereby potential trials for the up and coming months are presented, alongside a detailing of the proposed protocol that is designed by the sponsor or internally at the centre. The board, who are comprised of internal and external pharmacological professionals, review this representation, and have the ᤀ┄nal word on how safe, scientiᤀ┄cally valid and logistically possible the prospective trial is, and ultimately, if it shall be taken on by the organisation.
All focus group discussions were transcribed and analysed thematically at the end of each working week. Naturally this led to the realisation of certain patterns in the data, and a reordering of subsequent interviews to test the reproducibility of such trends. In the midst of interviewing clinical scientists it became evident that investors and pharmacologists utilise a diᤀ鸄erent language to conceptualise the pharmaceutical, whilst all the same anthropomorphizing it in an intriguing way. The research objective from this point onward thus became focussed upon how pharmaceutical actors develop a relationship with the compound, what the reasons for doing so are, and how this inᤀ┄uences other aspects of clinical pharmacology.
In accordance with the guidelines set by the American Anthropological Association, the identity of the phase I unit and the professionals within it have been anonymised. Participants have been attributed pseudonyms, whilst their respective job titles and gender, have been scrambled.
Limitations
Given that the ethnographic period was only seven weeks long, there were naturally some limitations to the research that unfortunately could not be overcome. The ᤀ┄rst issue was trying to keep up with pharmacological expertise, and to not dedicate too much time toward asking the scientists technical questions about their practice. This was an inevitably however, in order to facilitate a basic
understanding of scientiᤀ┄c processes, to be able to relate in part to the frustrations of the
pharmacologists with respect to their everyday practices. Conversely, there was a good amount of interest in myself as the anthropologist (which would not usually be a problem), however interviews often only lasted an hour, meaning a signiᤀ┄cant proportion of time was spent explaining my own position.
Secondly, the primary language of instruction at the centre is Dutch, a language not spoken by myself, which caused expected diᤀ搆culties. This was an issue both with respect to scientists not being able to articulate themselves as well as they might be able to in their mother tounge, as well as my own possible misrepresentation of their thoughts and ideas upon transcription. On a technical level this also led to my inability to integrate within conversations around the centre subtly, thus forsaking an opportunity to recognise technical ‘silos’ within the centre, and linguistic patterns.
Thirdly, the research was conducted within the conᤀ┄nes of the phase I centre, meaning that interviews could only take place upon appointment, in the midst of the clinical pharmacologists and their
colleagues’ understandably busy schedules. This usually meant that individuals and groups were interviewed in one of the meeting rooms for about an hour, before they got up and left to get back to work. This was not a major problem, as interviews could be continued another time formally or informally, yet on occasions the ᤀ┄ow of an interview was broken down due to this occurrence. Furthermore, sensitive or personal topics could understandably not be discussed at the workplace as they might have been outside of it.
A lack of opportunities to interview colleagues at the centre at length or repeatedly was signiᤀ┄cantly compensated by the sheer number of professionals interviewed. Overall, forty seven people participated in focus group discussions and/or interviews, which generated a vast amount of primary material, that upon transcription produced over 160,000 words of data. The limitation in this respect is that the selected comments, anecdotes and observations that are included within the body of this thesis, is comparably inᤀ┄nitesimal . Furthermore, the fraction of content that is present in the text is naturally what 7
I, the author, believes to be most interesting and relevant to the social life of the pharmaceutical project. Considering this thesis is concerned with the negative eᤀ鸄ects subjective intrusion has on research, it must be acknowledged that my own personal intervention in many ways shapes the argument and tone of the text. Just as it will later be explored how the experimental compound is compared to be the ‘baby’ of the investor as result of their personal attachment, it must be ceded that this thesis is in many
respects the baby of the author. Just as pharmacologists are also observed to ‘kill’ the compound in a ruthless way, the vast majority of primary material that provide the basis for this research, unfortunately had to experience a similar fate. It is hoped that the interpretation of the author is not so prevalent as to stiᤀ┄e the interpretation of the reader.
Finally, it must be noted that a signiᤀ┄cant limitation to this thesis is that only one side of a two sided story is told. That is, the pharmacologist and investor’s relation to the experimental compound. Although the interpretations of the former are the foundation for this paper (supplemented by primary materials), there appeared to be no way of presenting the pharmacologists’ point of view, without implicating the investors, whose beliefs and value systems are so distinctly opposite. These pharmaceutical actors are not located permanently at the phase I centre, and were thus not interviewed during the ethnographic period. It is true however that many of the pharmacologists (and other professionals) interviewed have worked for pharmaceutical companies, and experienced a personal relation to the compound
themselves, which is addressed at the beginning of chapter three. This in itself is an interesting phenomenon, and teaches us that there are many individuals who have experienced multiple perspectives about the drug development process by virtue of their diverse professional careers.
Nevertheless, more ethnographic research is needed within pharmaceutical companies and biotech start ups to locate the investors’ side of the story as it were, which may in turn substantiate or contravene the ᤀ┄ndings of this paper.
Chapter III
An ethnography of the phase I trial
The purpose of this chapter is to provide an ethnographic description of the phase I clinical trial, so that the later discussion that concerns the clinical pharmacologists and their relation to the experimental compound can be contextually located. What is signiᤀ┄cant (yet can unfortunately not be explored in detail) throughout the chapter, is that all professionals within the building must undergo a process of reᤀ┄exivity in order to ensure that personal or emotional interpretations toward the compound,
participants or process of the study, do not inᤀ┄uence the rational and objective spirit that is fundamental to the ‘gold standard’ of the clinical trial.
The centre
The site for this research is a well established phase I centre in the Netherlands that has been testing experimental compounds and formulations on humans for over thirty years. The site has experienced near exponential growth since its inauguration, and to accommodate this, the building and workforce has been upscaled considerably. There are over a hundred and twenty full time staᤀ鸄 working at the centre, and nowadays, around ᤀ┄fty trials are conducted each calendar year, with studies providing insight into multiple research areas including; neurology, psychiatry, immunology, dermatology, pain, and
cardiovascular studies.
The centre conducts phase I trials for various pharmaceutical sponsors and biotech startups from around the world. Although capital is generated from these contracts, all of which funds the institute, with 10% of the annual turnover dedicated to an R&D budget which facilitates in-house trials that are independently designed and executed, and usually involve an innovative methodology conceptualised by the pharmacologists themselves. The centre has well established relationships with various groups and departments based within nearby universities, and places particular impetus on education, and the furthering of pharmacological methodologies. As result, the organisation is uniquely positioned between academic and commercial worlds, with many at the company stressing the importance of balancing these interests in order to raise suᤀ搆cient revenue to keep the organisation alive, whilst maintaining a degree of scientiᤀ┄c innovativity for the pharmacologists it employs.
The building itself comprises of eight stories. The ground ᤀ┄oor is where trial subjects ᤀ┄rst enter the building, and are welcomed by reception. Besides the canteen, the second and third ᤀ┄oor is occupied by the clinical pharmacologists, business administration team, and operational and administrative staᤀ鸄, who work on computers most of the day, unless their presence is needed at one of the clinical trials. The
fourth ᤀ┄oor hosts the data management and statistic personnel, who are joined by the information technology and recruitment teams. Nurses typically scurry between the ᤀ┄fth and sixth ᤀ┄oor where subjects are given a medical check up before the trial in one of the screening rooms. The seventh and eighth ᤀ┄oor are dedicated for the trial subjects, who are given their own bedroom, en suite, and share communal areas and an outside decking to be comfortable during their stay. Naturally, physicians and nurses ᤀ┄lter in and out of these areas to monitor any physiological changes in the subjects bodies using various equipments.
The communal areas are usually inhabited by a handful of people who are occupied by typical daily activities such as watching television, browsing the internet, or studying. Within the ᤀ┄rst week of the research period I was startled to observe three elderly subjects drinking orange juice whilst glancing over the morning newspapers, wearing matching dressing gowns, surrounded by nurses behind a desk and physicians holding ᤀ┄ipcharts. The subjects were remarkably unphased and unaᤀ鸄ected by their
surrounding environment, despite also having their brain activity monitored by what appeared (to my layman observation) to be some sort of shower cap that sprouted electrodes from their heads in several directions . To the pharmacologists, and after a few days the subjects themselves, these situations 8
become an everyday norm. This is a point that should not be understated, as such a typical daily scene within the centre symbolises the seamless collision between the social and the technical that
pharmacologists must uphold for the importance of external validity, that is to which extent the results of the trial are generalizable to other environments and populations in the ‘real world’. All the while,
pharmacologists maintain a clear distinction between the social and technical during the trial in order to conduct unbiased, objective investigation. Although these professionals manage to do so at ease, it is worth noting that undertaking a position of objectivity and neutrality, whilst testing experimental compounds on humans living in simulated environments for the ᤀ┄rst time, naturally requires a considerable measure of control and professionalism. It is this conscious yet perhaps increasingly instinctive behaviour on behalf of the pharmacologist that facilitates their own collective detachment from the various compounds that are tested in the building, which is later explored in chapter four. Next, is a mapping of the phase I trial itself.
The phase I trial
Every individual at the building contributes in some way or another to the execution of the phase I clinical trial. The trial itself tests experimental compounds in humans for the ᤀ┄rst time, and typically includes between ten and twenty ᤀ┄ve participants.
The purpose of the trial is to discover if the compound or formulation is safe for human consumption by determining what potential side eᤀ鸄ects arise, how the body reacts to the drug (pharmacodynamics), and
simultaneously, how the drug is aᤀ鸄ected by the body (pharmacokinetics). As well as this, early signs of eᤀ搆cacy are monitored, sometimes utilizing pharmacometric expertise which creates mathematical models to predict how the drug will perform on alternate populations (in terms of size and patient variability). This is not always considered essential to the study, depending on the preferences of the sponsor, but is useful at determining what volume of the compound should be administered during the subsequent phase II study. A typical phase I trial is ‘double-blind’, meaning that neither the subject, pharmacologist, or nurse will be aware of which half of the trial group has been administered with the active compound, and which has been given the placebo. Following either the protocol or a mutual decision made by the sponsor and centre, various dosages are administered to the subject increasingly, until side eᤀ鸄ects are observed. As mentioned, the trial is a collaborative eᤀ鸄ort, and involves diᤀ鸄erent sets of expertise at various stages, as depicted in ᤀ┄gure one. Explaining the process chronologically and in it’s entirety requires two trajectories, as before the compound reaches the site and the human body, the participants and the sponsor must both follow expectedly alternate pathways. On the commercial side,
the sponsor ᤀ┄rst contacts the centre to enquire about conducting a phase I trial to test their prospective compound, and after months of correspondence, a series of face to face meetings take place whereby a negotiation is settled, and a timeline and protocol drafted. As a business developer at the organisation explained:
We do not meet face to face immediately, we do a lot of calls, a lot of emailing. You read and review material, they come for a visit, we might go to their o႐ces to meet the rest of the team so we just wait a little bit until somebody comes back the feedback so it takes a lot of meeting and talking and waiting. It is not like seven months of continuous discussions, it’s a slow progression.
Once a deal is struck, the prospective trial is presented to the management team and Scientiᤀ┄c Advisory Board (SAB), a panel of external pharmacological experts who assess the safety and feasibility of the trial in terms of logistics and operation. The trial is presented by the designated project leader who is well researched on the topic, and has had correspondence with the sponsor. These meetings take place once a fortnight in the auditorium of the centre and attract almost all pharmacologists who by nature are interested in the trial itself and are not hesitant to weigh in with scrupulous questioning to ensure no black boxes are left unopened with respect to potential pharmacological oversight.
The participant trajectory involves a totally diᤀ鸄erent set of expertise. The centre itself has a database of over 40,000 available volunteers who are signed up after hearing about the prospect of generating an income ranging typically from ᤀ┄ve hundred to two thousand euros . Other participants, primarily the 9
elderly, are also interested in contributing toward the furthering of medicine and meeting new people at the centre. Potential subjects are usually attracted to the trial upon discovering the possibility of participating via newspaper advertisements, stalls at universities, and the institute's website. The recruitment team is made up of seven people who operate the phone line and run the company website designed especially for potential volunteers. As well as this, recruitment also form networks with patient groups and organisations who are cooperative on the premise of discovering possible treatments for their respective disorder, illness or disease. For recruitment there is some diᤀ搆culty at traversing the ethical grey areas that exist between the subject and the trial, as a long serving recruiter explained:
So it would be really easy to advertise here, to say you can ‘earn for your summer holiday here’, but that is not ethical. So we are looking for the ࿌ne line, we once got whistled back by the ethical commission because the font of the (monetary) amount was in bold, and the rest was not. So, do we do advertising? Well yes. We use media, newspapers and the internet to advertise our studies, but
9 There is a ninety day rule in place that exempts subjects from generating any kind of salary from the the trial, and
the actual content of the advertisements is fairly honest and not really with shouting letters and everything, because we are not allowed to.
Recruitment also deals with the signiᤀ┄cant responsibility of recruiting subjects who are ᤀ┄t for the trial and willing to participate, rather than feeling forced to for ᤀ┄nancial reasons. Especially since the recent incident in Rennes that took the life of one healthy volunteer, and hospitalised ᤀ┄ve others, managing the 10
expectations of the subjects is also of utmost importance, as ‘drop outs’ during the trial severely compromise the validity of the study. Once the potential subject is admitted by recruitment, they are passed on to the screening department, a team of nurses and physicians who perform a routine medical check up to ensure that the person ᤀ┄ts the criteria for the trial. Unlike a usual check up however, the primary focus is not to ᤀ┄nd general health defects, but rather to determine if these defects are relevant enough to exclude them from the trial. As a physician explained;
How you screen, it is not per se if the person is healthy. It is more to do with people being suitable to join the study. Sometimes for instance if you see a little bit of blood in the urine, that could be a possible prostate problem for a male. It could be a reason to do some extra tests. But here you write down, "not clinically signi࿌cant", because it doesn't bother the test, the study. If I think they are not suitable enough I call the physician, and tell them. If they are not healthy, then it's done. Recently we had a guy with horrible heart murmurs all over the place. It's just not good to have them included. It's just not good.
For all parties it is not good at all to have considerably unhealthy people participate in the trial, as side eᤀ鸄ects independent of the compound itself occur that may not be distinguishable from the eᤀ鸄ects of the administered medication, thus compromising the validity of the trial that after all, is only meant to determine if the compound is safe for consumption in a small group of healthy volunteers. After subjects have been screened, everything is in place for the trial to begin. The project leader now takes
responsibility for introducing the subjects to what the study entails, and essentially, how they should behave and what kind of medical intervention they should expect. Some days after, the subjects return, and are administered with either the compound or placebo by a registered physician. For the duration of their stay, the nurses are present 24/7 to both ensure the safety and wellbeing of the participant, whilst also noting any clinically signiᤀ┄cant physiological changes or adverse side eᤀ鸄ects the subject
experiences
After talking with the nurses extensively, it became clear that their position is somewhat diᤀ鸄erent to their own prior nursing responsibilities in hospitals and nursing homes, and that adapting to the scientiᤀ┄c environment of the centre is a fundamental aspect of their profession. As a nurse elaborated:
Put it this way, I felt like I had landed on another planet. First of all you work with healthy volunteers most of the time, second, everything is done not only in english but in scienti࿌c english so that took some getting used to. So yes, it is di࿌erent in so many aspects. The timing is also so much more important than in the hospital, that you are punctual… you have to have a di࿌erent mindset really to work here. It takes about two months until you grasp what's expected of you.
As chapter four will investigate, this thesis concentrates on the relationship between investors and their compound and how an anthropomorphosis of the inanimate creates a social dimension to the clinical trial that has been relatively unexplored. An important point is that data proves to be the medium which allows (or prevents) the pharmaceutical to travel. Statistical evidence, analysis and predictions about the potential of the compound facilitate its capability to move to the next phase of the drug development process. Therefore, the accuracy and reliability of data is of utmost importance to both the sponsor, and the clinical research organisation. Another nurse at the centre reᤀ┄ected upon a tension between the importance of this data, and the health of the subject:
We are here to generate data, that is our work. The thing is, connected to the data we see faces that most other people don’t see, and so that’s our dilemma sometimes. Yes we want data, yes we want everything to be perfect but we also see someone who is miserable and sometimes that creates a tension. It is a duty to stand up for your subjects, to say enough is enough.
Just as recruitment and screening face the responsibility of admitting people to the trial with the appropriate mindset for the experiment, nurses undertake the duty of looking after the interests of the subject when others in the building are naturally more concerned with the data they are employed to analyse and interpret. Project leaders, who run the entire operation of the trial and are the focal point of this thesis, experience a similar tension:
As a project leader sometimes I have the dilemma that if you’re dosing people and you’re already seeing side e࿌ects, the sponsor and principal investigator decides to go another (dosage) level higher. You’re the only one who has to do it. You’re not the one that is deciding, but you are the one that has to communicate it, and sometimes that is a dilemma, sometimes it is too much of an ethical question, and sometimes I just don’t want to do it.
Such a dilemma is commonplace for project leaders who often have to defend the rights of the subject by resisting sponsor demands for the participant to ingest too many capsules, or undergo several biopsy procedures. As the thesis will later explore, there is a constant strain between the pharmacological interest in the trial, and the sponsor’s obsession with their own compound. The trial period comes to an end when the proposed milestones outlined within the study protocol are met, or alternatively if the dosage level has induced adverse side eᤀ鸄ects that are too severe for the trial to continue. The generated data is handed to data management, who begin the process of ‘cleaning the data’, which involves a correction of erroneous data observed as anomalies. A team of over twenty people receive various forms of data generated by the medical check up during screening, physiological measurements and side eᤀ鸄ects noted by nurses, and all data that is registered in the lab, and by the various equipments used during the study. As an analyst at the centre explained:
You have di࿌erent stages, you’ve got the collecting of the data, here a lot of things go wrong, and Murphy says they will. Then there are several steps to clean that mess, and at the end of the line there is the cleanest data we can have. That is when you can start doing the science. It’s a long cleaning process, to make data collected from humans - which is always prone to errors, into something clean and workable.
Once the data is clean, the database is locked, and is ready to be analysed by statisticians. Here the results that matter for the investor are produced via several analytical techniques and models that ultimately provide a statistical overview that details if the compound achieves its desired eᤀ鸄ect, and how so. Like all professionals at the centre, statisticians are put under immense pressure to yield results for sponsors who are eager to get their compound to the next stage of the drug development process. As a statistician detailed:
Sponsors want the data too quickly and then later on you discover [gasping] “I used the wrong model for my analysis" and things like that. There is a lot of pressure, especially when we have had a few clients who have meetings with their shareholders, and they want to present results to them..
Sometimes it is too fast and you either work with data that is not clean, or analysis you have very little time to think about or contemplate. Then you do it, and later on you think "Oh I shouldn't have done that".
Giving accurate estimates as to when the data will be analysed is not straightforward given the multiple complexities within the dataset itself, and the tools and models that often have to be invented on-site for an analysis to be possible. At this juncture, pharmacometric expertise may also be employed in
accordance with the requisites of the sponsor. Pharmacometrics involves the creation and utilisation of mathematical models that are able to predict how the compound will perform on alternate population
groups in terms of size and variability (gender, age, height, weight, enzyme conversion rate etc). As a pharmacometrician explained during an interview:
As you are well aware, a lot of drugs never make it to the market, and a large portion of the failures happen during phase II, phase III, when we go from healthy volunteers to patients. We don't do that too much here but predicting why it goes wrong, saves ࿌fteen years of research, if you can do that at an early stage. That's what it is based upon.
The reality on many occasions for pharmacometricians however is that the sponsor is hesitant to delve into the data to such an extent, most imaginably for a lack of conᤀ┄dence toward deviating from the conventional, linear protocol. There is an element of uncertainty that perhaps obstructs the relationship between the investor and pharmacologist, which is produced in part by an ‘informational asymmetry’ (Ravelli, 2011) that exists between them:
If I ࿌nd no e࿌ect and I don't see that if increasing the dosage reaches safety problems, that means that we should not continue with the higher dose. I leave it up to them to make the call that they should kill the drug. That's not up to me obviously. I do provide them with my kind of knowledge and my study design for the next study, and if I think well, it's useless, I’ll tell them “let's not do that.”
After the statistics are completed, the clinical study report (CSR) is either written by the project leader, or the sponsor themselves. Crucially, the CSR must be published within six months of the study’s
completion, in accordance with the Declaration of Helsinki. Once again however, such protocol is not always routinely followed, and many pharmacologists complain that sponsors are somewhat selective about that which they choose to include and exclude, or rather, overemphasise and underemphasise, about the results of the trial. A project leader reᤀ┄ected upon this occurrence whilst also (somewhat inadvertently) surmising the ambiguous relationship between the investor and pharmacologist that is predicated upon a sharing of knowledge about the compound that contractually intertwines them:
We are a bit stubborn. We have an attitude that we do know how to do clinical research and we do, but of course they also know how to do research so that is also something that interferes. It is a bias, and that is the luxury of being here, we do not have the investment, we do not care. If there are strange side e࿌ects it will eventually show up, I mean, you cannot hide it. The other side of the story is that at some level sponsors try to question if what happens is really an adverse event, and they want to reword the discussion, sometimes they don't want to acknowledge it, so word it di࿌erently. In the end they have commercial interests, it makes sense. If they disagree with how we interpret
something, it is written down and it is there forever. They really focus on re-wording, and many of us are not native speakers, so it can be dubious.
For all of the professionals that work within the centre, there is an ever present tension between the demands of the sponsor and the functionality of the trial. This tension plays out bureaucratically and electronically via the back and forth of queries and emails, yet is richly social and personal in dimension upon taking a closer look at the way in which investors and pharmacologists relate to the compound in diametrically opposing ways. The next chapter will investigate ᤀ┄rst the relationship between the investor and the compound, and how due to sustained pressure to get the potential medication to the market, a subjective and emotional attachment is forged with it. Second it is analysed how for pharmacologists, the opposite is true, as a dissociation from the compound occurs in order to construct and maintain a collective habitus of scientiᤀ┄c objectivity and integrity.
Chapter IV
How investors and pharmacologists relate to the compound
This chapter addresses the main focus of this thesis, which is that during the phase I clinical trial, the compound that is tested in the building is attributed a life of its own by both the investor and the pharmacologist, yet in notably contrasting ways. Generally, both sets of individuals share the mutual interest of testing the compound for signs of safety and early eᤀ搆cacy, as is the reason for the contractual obligation that binds them. However, the personal motivations behind this shared
understanding are not so aligned. For the investor, what is of utmost importance is that the compound gets to the next phase of the drug development process. For the pharmacologist, the compound is less important, as it is the trial which should be ᤀ┄awlessly executed, and must yield the most accurate results, regardless of outcome. This diᤀ鸄erence in interest crucially surmounts to a divergence in the perceived value of the compound as an object, and what its social potential may be. Such a value incoherence is nevertheless anthropomorphised by both sets of actors. For the investor, a long term subjective and personal attachment with the compound is developed over time and is facilitated by ᤀ┄nancial investment. Pharmacologists on the other hand, (with less ᤀ┄nancial interest in the compound), remain rooted to rational scientiᤀ┄c practice, and experience a detachment from such involvement, which is underscored by the pharmacological responsibility to ‘kill’ compounds that do not
demonstrate evidence of safety and eᤀ搆cacy. In short, for the compound to have a social life at all - it must be believed in. If such evidence is not forthcoming, belief ceases to exist for the pharmacologist, whereas for the ᤀ┄nancial investor who has far more at stake, giving up such faith can be something of a personal tragedy.
The ᤀ┄rst part of the chapter will introduce the experienced attachment and subsequent relationship sometimes forged between the investors and their compound. Second, the pharmacologists’ own relationship with the compound, which is briefer and characterised by detachment, is discussed. Finally, the way in which these perceptual diᤀ鸄erences produce a tension that is mitigated by shared mutual understanding is observed. Essentially it is concluded that despite the polarity of value coherence made about the compound itself, both parties will strike a balance between these competing interests in accordance with the transfer of expertise that brings them together.
An attachment to the compound
During a phase I clinical trial, investors in the potential compound being tested may develop an attachment toward it that is subjective and emotional, which at least to the pharmacologist is
