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Saturday, 22 April 2017

Science in Lucy Prebble’s The Effect

The Effect opened at the Royal National Theatre, London, in a co-production with Headlong Theatre Company, directed by Rupert Goold, on 12 November 2012. It was written by Lucy Prebble, who had scored a major critical success with Enron in 2009. The cast were Anastasia Hille as Doctor Lorna James and Tom Goodman-Hill as Dr Toby Sealey, Billie Piper as Connie Hall and Jonjo O’Neill as Tristan Frey. The Effect is set in a drugs testing facility. Triallists Connie and Tristan have volunteered to stay in the facility (a hospital) for a four or five week trial period to undergo testing of a new antidepressant. The drugs are administered by Dr Lorna James, and the trial is overseen by Dr Toby Sealey. The play itself is set up like a drugs trial, reflected in the text (such as references to the age, weight and height of the characters in the list of characters, and the stage direction at the start of the play ‘experiment begins’) and the performance, with Connie’s heart rate, for example apparently visible or audible for the audience to see / hear at appropriate moments in the play). 

With its medical context, The Effect is placed on the spectrum of plays that deal with science in one way or another. Kirsten Shepherd-Barr points out that plays that deal with science have been around for several centuries, but that since the mid-1990s, there has been an unprecedented wave of such plays, which has not abated since (2006: 1). The science plays come from Britain,  the USA, France, Germany, Switzerland, Greece and other European countries, and encompass ‘neurology, physics, biology, evolution, genetics, reproductive technology, epidemiology, biochemistry, mathematics, and astronomy’ (2006: 1). Shepherd-Barr identifies a number of recurrent features in science plays: they cast the scientist as hero or villain (or indeed both), they engage with ‘real’ scientific ideas, they portray complex ethical discussion, and they demonstrate an ‘interdependence of form and content that often relies on performance to convey the science’ (2006: 2). As far as the form of science plays is concerned, Shepherd-Barr notes the diversity, ranging from realism to documentary theatre, from Brechtian theatre to non-realistic approaches, often combining ‘textual richness with scenic restraint’ (2006: 2). A leading exponent of science in theatre plays, Carl Djerassi, is keen to ensure that at least in his plays, the science is as accurately presented as possible. In that sense his plays are also didactic. 
At the core of this article is an exploration of the extent to which the science in The Effect is accurate, of the instances where the play deviates from knowledge, approaches, protocol and scenarios in science as practiced today, and of possible reasons and impact of such accuracy or deviation. The article analyses the play in terms of the institutional context it presents, the relationship of the scientists and the volunteers, common assumptions about psychology, and the specific procedures of the trial presented in the play. This exploration is based on discussing the play with Dr Paul Grassby (Head of the School of Pharmacology, University of Lincoln), Dr Graham Lappin (then Reader, School of Pharmacology, University of Lincoln) on 13 October 2013 in person, and Dr. Wayne Macfadden (then Senior Medical Director, Hoffman-La Roche Neuroscience) on 17 October 2013 via skype.        

Paul Grassby
Graham Lappin

The institutional context
The Effect identifies Connie and Tristan as healthy volunteers who are to stay in the trial institution, a part of a hospital, for four weeks for the doctors running the trial to establish the impact of a new antidepressant. The volunteers undergo a series of pre-trial tests, then the drugs are administered in increasing doses, and further measures are taken to establish the impact of the drugs on the volunteers. Paul Grassby agrees that clinical trials at their beginning stage are expected to work with people who are healthy.  Wayne Macfadden expands on this by pointing out that ‘after a drug is shown to be not dangerous in animals, it progresses to healthy volunteers to determine what the maximum tolerated dose is’. According to both Grassby and Macfadden, this is a relatively short procedure, and would not take a month, as the trial in the play.  In addition to establishing the doses that are safe for humans to take, the first phase in current trial practice tests for pharmacokinetics, ‘what the body does to the drug’, which is ‘the movement of the drug into, through, and out of the body’ (reference).  Once safety and pharmacokinetics have been established in healthy volunteers, pharmaceutical companies will start testing the new drug on volunteers who have actually had the disease, not another group of healthy volunteers.  Macfadden goes on to point out that the purpose of the anti-depressant medication that is being developed in the context of Prebble’s play is to improve symptoms in people who are suffering from a Major Depressive Disorder, as described in DSM-5: ‘therefore one wouldn’t give it to a healthy person as it wouldn’t really tell you anything, as you wouldn’t of course expect to improve their mood as they are not clinically depressed’.  Macfadden’s observation in this context relates to Grassby’s position that what is presented in the play is not really a clinical trial but more of a research project.  ‘It is the first experimental attempt to put the active ingredient into a human and it is not a rigorous randomized, double blind clinical trial’. 

Thus in terms of the scenario that provides the frame for The Effect, the play collapses several stages of a real-life trial, ranging from pre-trial experiment via test for safety and pharmacokinetics with healthy volunteers, to the long-term trial with volunteers who are suffering from the symptoms the drug is supposed to address. When the doctors talk amongst each other, Toby says ‘an antidepressant effect in healthy volunteers.  Pretty extraordinary.’ (2012: 23)  This is a further instance to suggest that the scenario in The Effect is a research project and not a clinical trial because as Macfadden says, ‘presumably this drug is being tested for a Health Authority approval-  so one wouldn’t primarily be studying its psychoactive effects in healthy people’.  In  drug trial testing at the clinical trial stage researchers would be looking at ill people. ‘They would not be doing psychiatric depression rating scales in normal healthy individuals so again this points to the fact that what they should actually be doing is not a clinical trial but only testing the drug for its safety and tolerability’. The length of the trial period in The Effect is also contested by the experts: what happens in the play suggests a pre-trial research project or testing for safety and pharmacokinetics, which would not take four weeks.  

The play suggests that there are more male volunteers than female ones.  Grassby points out that the rule of thumb is that the first participants in a trial or experiment are always male. Pharmaceutical companies do not use females at all, because for new drugs, studies of how an unborn foetus may be affected by the drug cannot have been carried out yet.  There may be exceptions, depending on the general target for the drug.  ‘If you had a small number of females in there, I don’t think you will be breaking some big rules, but they are mostly males at the first stage’. Macfadden agrees that there are usually more men, and in the case of female volunteers, the testing institutions have to ensure as best as they can that the female volunteers are not pregnant and will not get pregnant for the duration of the trial. 

Further within this context of the institutional conditions surrounding drugs trials, Connie and Tristan discuss that for some projects English has to be the first language and subjects have to be articulate.  This assumption probably implies that these subjects will be able to express the kinds of experiences that they have in relation to the drugs—by further implication, for other kinds of drugs they might the companies might select volunteers who do not fit that description.  Lappin points out that in clinical trials there is a need for informed consent.  ‘That means that subjects usually have to read quite a lot of material before they start and then understand it before they sign off’.  Thus all trials require a certain level of literacy from their subjects. It should be noted, however, that, as Grassby comments, much of this work of clinical trials is sub-contracted by pharmaceutical companies and many clinical trial units that they set up tend to be in the poorer areas ‘so they tend to capture people who do this for money’.

Billie Piper and Jonjo O'Neill in Lucy Prebble's The Effect

So far, the following picture about the use of science in The Effect emerges: the scenario that Prebble sets up for The Effect is somewhere between first experiment and first trial phase with healthy subjects to test for security. The four-week duration of the trial is not compatible with either experiment or first trial phase. The socio-political context is similarly ambiguous regarding the information about level of literacy required, and with the presence of a female subject more of an exception in real life situations.  

Towards the end of the play, when an overdose of the drug has had devastating effects on Tristan, Dr Sealey discusses events with Dr James and concludes that ‘nothing will be published obviously’ (2012:  97). Macfadden wonders whether this is an indication that the researchers would not be publishing all the results: in a real- life context that would not be acceptable.  The question then arises as to the personal interest of the doctors involved in this case with the outcome of the project and here Macfadden comments that physicians like Dr James should not have any financial interest in whether the trial succeeds or not because she is presumably paid only for her time so it shouldn’t matter to her whether the drug works out or not.  For Dr Sealey the matter is likely to be different: ‘he is probably a stockholder in the company and he would want the tests to work and that is why in the real life scenario he should not have anything to do with the actual patient care and he would certainly not know which patient was receiving placebo and which was not’.  Macfadden emphasises that companies (sponsors of research) are very keen on monitoring their procedures very strictly: 

In general, clinical trials are closely monitored by the sponsors, as information may need to be provided to health authorities. To start with, the placebos are supposed to look exactly like and taste like the real drug. The unblinding codes are strictly maintained, so nobody in the company knows who is on active drug and who is receiving an active drug, unless there is an urgent safety issue. Then a patient may be ‘unblinded’, and the treating physician is informed about what they are receiving. There are also specific contractual arrangements with the investigators; they must not be overpaid, nor given extra financial incentives. They must be paid only for their work on the project. For example, it is forbidden to give investigators extra money if they recruit more patients than other investigators.  Finally, there is an obligation to publish all the data within 12 months of the end of the study. 

The scientist – volunteer relationship
In the early stages of the trial, independent of whether it is an experiment or whether it is a clinical trial, the question is whether the scientists running the experiment would be on the ground with the subjects at the stage of their admission to the trial facility, doing the blood pressure tests, swabs, giving medicines and discussing their questions, or would this be done by their assistants only?  The very first encounter in the play between clinician and volunteer, Dr James and Connie, gives rise already to the question as to what kind of scenario the play is taking as its focus: where, in a real pharmaceutical company testing its new drugs on humans, would we find the contexts described in the play? The play begins with Dr James asking Connie: ‘have you ever suffered from depression?’ (2012: 5).   

The play then continues with the discussion between Dr James and Connie of what it means to be depressed and whether Connie herself is depressed.  Dr James proceeds to ask Connie about pregnancy, contraception, smoking, drinking, drugs, medicines, irritable bowel syndrome, cancer (specifically of throat, lungs and skin), arthritis and diabetes.  What the play seems to be covering here is anything that could possibly have an effect or be related to the drug in question, or even further, where they do not expect anything but they are testing for those influences anyway.  According to Grassby and Macfadden, this range of questions, and the fact that the questions are asked by the doctor involved in the trial, rather than an assistant of some kind, makes sense in comparison to their experience in drugs trials. Lappin adds that there would be a very close relationship with patients and medical staff at this first stage.  

However, Grassby, Lappin and Macfadden also agree that the play shows too much of familiarity between the doctor and the patients, which according to Macfadden,

most people in the profession would probably view as inappropriate doctor/patient contact, for example Dr James telling Connie about her previous affairs and her love life [2012: 61-62].  Even in a psychotherapy situation most people would view such behaviour as not within the boundaries of normal practice.  In a clinical trial it is even more important to to remain neutral to the subject, and ask open ended questions- so their responses are not influenced by their personal feelings towards the investigator. 

Jonjo O'Neill and Anastasia Hille in The Effect

Especially the scene in which Dr James suggests that the male volunteer, Tristan, could give the urine sample while she is present is certainly not part of what would happen in real medical circumstances, as Lappin points out ‘those samples are not normally supervised, there are rooms that you go into and you produce the samples and they collect it, and they wouldn’t mix male and female’. 

A further example of this over-familiarity is the long joke that Dr James tells Connie

There is this medic at a conference and he has fallen for a girl there who hasn’t looked twice at him.  He knows dopamine is the initial trigger for falling in love but also that dopamine is stimulated a new, exciting experiences.  To try and get the girl he arranges for them to go bungee jumping together to set up his own chemical reaction.  The instructor ties them together and they stand over this incredible valley and he has got his arms around her and they fall long into this incredible, adrenalin/filled rush – and their dopamine levels go higher.  Eventually they get lifted back onto the bridge, they get their breath back and he looks into her eyes and says, ‘wasn’t that amazing!’ and breathless she answers ‘yes and isn’t the instructor handsome!’  (2012:  22)

Macfadden observes that it is not so much the question of whether this is an in-joke amongst psychiatrists but that this is an instance where more intimate conversation takes place and ‘a breaching of the objectivity that one would expect from a physician interacting with a subject when testing a psychiatric medicine’.  

All three specialists confirm that scientists involved in drugs trials, no matter at what stage, would never know which patient received the real drug and which received a placebo. It is thus not realistic that Dr James knows that Tristan is receiving a placebo and not the drug. In consequence, it is equally not realistic that her own reporting is tested as well for bias (i.e., Tristan in fact gets the drug, not the placebo). Macfadden explains that this would not happen in real life scenarios,

as you can’t test investigators that way and especially because those involved as researchers in such a procedure would never be trusted with the knowledge of who is getting the real drug and who is getting the placebo—not until the end of the experiment—as that would introduce too much bias, especially in psychiatry where many patients respond to a placebo pill only, and thus one needs to be as neutral as possible.

Knowledge of and assumptions about psychology
Across the play, the volunteers, Connie and Tristan, as well as the scientists, Dr James and Dr Sealey, talk about the testing of drug-related aspects of psychology and psychiatry in general, and with regard to depression in particular. Given the play’s emphasis on the volunteers, I will consider them first in this context. Connie is a psychology student, and asks Dr James directly whether her knowledge of the Stroop test may or may not interfere with the results. Dr James explains: ‘In most cases being aware of your own bias doesn’t actually mean you can affect that bias’ (2012: 19). Macfadden confirms this. Grassby, however, is of the opinion that if the subject knows the test, knowledge can be a problem.  In some cases Macfadden adds ‘if you repeat a psychological test there is a learning effect the second time around’. He argues that knowing about the contents of tests in general may not matter as long as the subject did not undergo the test too recently. 

The play demonstrates in dramatically interesting detail how the two volunteers break every rule in the book.  They go out of the prescribed area, they smoke, they use their phones, and they have sex.  Should they not be eliminated from the data set?  Lappin explains, first of all, that the rule not to use mobile phones is not something he recognises from the drugs trials he was involved in. In terms of the problematic behaviour, he points out that volunteers get compensated financially for doing a trial. In case of minor infringements of their contracts, they get fined and the money they receive in the end goes down. In case of major infringements they are excluded from the trial and do not receive any money.  The infringements presented in the play would certainly count as major.  Macfadden confirms that on the safety trials it might be appropriate to have volunteers in overnight and if one where to lose a certain person for hours at a time, one may need to eliminate them but it is a judgement call of the investigator.  ‘If, however, they are missing for 12 hours one would certainly eliminate them and then they might be removed from the project as unreliable’.  Macfadden adds that in describing the experiment, the assumption is that there might be ‘protocol violators’ and the scientists may need to exclude those person’s data and start fresh with another person until they have the requisite number of subjects necessary.  Therefore in those properly protocoled experiments it would not ruin an experiment if one or two subjects had to be removed from the project.  

The play references general attitudes towards mental illness with the assumption that mentally ill patients rock to and fro (2012: 31).  Grassby comments that such a pattern of movement is normally due to the side effects of the drugs they are given, anti-psychotics, and not part of the mental illness itself.  Lappin adds that there is a whole range of repetitive behaviour, with rocking or walking up and down among them. According to Grassby, patients know that they are doing it and could try to stop doing it for a short period of time.  Macfadden explains that people with severe mental illness like schizophrenia may rock back and forth, but medication can make this worse.  

The constellations in the play are interactions between the volunteers, Connie and Tristan, or between Dr James and one or both of the volunteers, and interactions between Dr James and her line manager, Dr Toby Sealey. They discuss the rationale behind the development of new drugs, with Toby arguing: ‘ ‘It’s why we are developing new generations of ADs in the first place’ (2012: 24).  Macfadden comments that pharmaceutical companies attempt to develop improved, differentiated products.  Toby wants to be associated with something that is eventually improved.  In the same context Dr James continues with ‘Because the old ones have been discredited’, to which Toby responds: ‘‘No they haven’t been discredited, the studies that discredited our original trials have themselves been discredited now’ (2012: 24).  Macfadden comments that there is inaccuracy here, because nothing has really been discredited per-se regarding antidepressant clinical trials, although there have been different interpretations of the data through the years.  

The play also references the image of psychiatry as a discipline within medicine. In a long speech ‘at an industry event’ (2012: 28), Dr Sealey introduces himself like this: ‘I am Toby, I ‘m a psychiatrist, I’m afraid’ (2012: 28).  Then he talks about the serious representatives of medicine, the heart surgeons, in comparison to the Cinderella of medicine, psychiatry.  Psychiatrist Macfadden confirms that psychiatry is indeed commonly disparaged by other specialities in medicine because it is not always an evidence-based science and there are a lot of variations in clinical practice amongst psychiatrists. 
Tom Goodman-Hill in The Effect
 For this speech, Toby brings a real brain in a bucket with him. Macfadden find this unusual, arguing that it is also possibly unethical & maybe illegal: ‘you just can’t harvest body parts for the purpose of a talk’.

The actual drugs trial
When Dr James administers the first dose, 25 milligrammes of the agent RLU37, she gives Tristan a pill ‘that has been emptied into a plastic cup and then a plastic cup of water to wash it down with’ (2012: 12). Dr James says ‘5, 4, 3, 2, 1’, he then swallows it, his mouth is checked, Connie is next, Dr James indicates she should wait, she does. Dr James repeats her ‘5, 4, 3, 2, 1’. ‘ Connie takes hers, her mouth is checked, it continues theoretically with other volunteers’ (2012: 86).  Macfadden comments on this description of the process in the play as accurate if it were a drug trial, but possibly a little too elaborate for the testing for security that he considers the scenario in the play to represent. Lappin also notes in the context of the medical tests and their application that what normally would happen is that one person is dosed and then a team would wait for several hours to give the same dose and medication to the next person.  ‘That is a rule that they have to stagger because if they give everybody the dose and then there is a problem then they will all have the problem.  If you stagger them, only one gets the problem’.

In the play the dosage increases from 20-50 milligramme and so on upwards and later goes on to 50-100-150 milligrammes.  Macfadden comments that this is what would indeed happen, it is called a single ascending dose and a multiple ascending dose, which is the format in which one would use to test the safety intolerability and try to find out the maximum tolerated dose when people start to get side effects.   

The play suggests that nicotine inflates dopamine levels.  Macfadden comments that nicotine stimulates dopamine but not correct to say that it elevates dopamine for ‘hours’.  Connie and Tristan talk about the telemetry devices which they themselves detach and reattach.  According to Macfadden this is possible but the investigator would know when exactly at what time it came off and exactly at time it was put on again just as doctors would definitely not know who is on the placebo and who is not on the real drug and so there is no opportunity for them to tell the subjects whether they are on placebo or not.  Macfadden adds here that in the US it is considered unethical of the doctors to give placebos in the first place so Dr James’s comments in this regard would not be applicable to the US but might apply in the UK.  The side effects that the play mentions are irritability, paranoia, aggression, extra blinking response. They are the type of thing one would want to see early in a healthy volunteer, maybe in a single day but again not in a month long locked procedure. 

Anastasia Hille and Billie Piper in The Effect
Towards the end of the play, when Connie and Tristan have developed a love relationship and are not sure whether their feelings are real or the result of the drugs, we have the situation where Connie gets her tablets, another increase of the dose.  The doctor fails to check her mouth, Connie rushes to Tristan and kisses him full on the mouth. She has kept her pill in her mouth and in the kiss transfers it to him.  She assumes that he is given the placebo and wants him to have the real drug. However, he has been getting the drug all along, so on this occasion in effect he gets a major increase of the dose that he had been given before. He should have been going from 200 to 250, but does go from 200 to 500. Within seconds, Tristan ‘makes a strange sound, he staggers, loses consciousness, falls to the fall, stiffens.  His limbs jerk and twitch, his mouth gurns, he is fitting.  He bleeds from his mouth and wets himself, it is horrific’ (89-90).  In this context the experts comment that it is not likely that a patient will be bolting away and transferring a pill to another patient like this because it is more likely that they are receiving their pills independent of each other:  ‘typically it is a relatively private encounter between the study staff and subject when you give the person the medicine’ (Macfadden).  One reason for this is that one would not want to see what the other person is getting.  Lappin confirms that to go from fairly mild symptoms to symptoms described in the play by more than doubling the dose is extremely unlikely.  Grassby adds that the kind of side effects or the amount of side effects could happen but they would not happen that fast.  

Tristan then suffers from ‘transient global amnesia’ and he also has got ‘tardive dyskinesia’.  Macfadden comments that with tardive dyskinesia people can rock back and forth but that is the condition that people can get when they take anti-psychotic medications usually at a high dose for a very long time.  This effect would not likely happen after a single dose in such an individual even if it is a very high dose.  This is medically incorrect for a number of reasons: the effect would be coming from a different kind of medication and people need to take higher doses over a long period of time.  The amnesia is described as transient. Transient means, according to Macfadden, that it fades away so it should decrease but it does not seem to decrease in Tristan: so there is an inconsistency there.  The description of Tristan’s symptoms rather suggests that he suffered a ‘cerebral vascular incident, i.e., lack of blood flow to the brain’.  The other inconsistency is that the play suggests that Tristan has undergone a blood transfusion. That is strictly speaking not accurate ‘as in the case of an overdose like this one would not get a blood transfusion but a dialysis’.  

The play reveals that Tristan had a history of seizures in childhood, which was undisclosed (2012: 96) and Dr Sealey blames the strong effect of the overdose on that. Macfadden comments this is an example of somebody who may be hiding symptoms for the purpose of being eligible for a clinical trial.  It was not discussed whether the trial team would rely on self-disclosure or whether they would ask for medical records of the volunteers.  

The end of the play suggests in the stage directions that Tristan has recovered sufficiently to be discharged from hospital, but he remains vulnerable, his physicality is of a different man without some of the former bounce. It is left unclear whether it is something that he would be like forever, whether he is forever damaged in some form, or whether this is something that he is like now and there might be a chance of further improvement.  Macfadden points out that this is unlikely to be the result of a single dose but it is not impossible because the overdose might have caused a minor stroke, which would in turn leave more permanent damage.

To conclude, Macfadden thinks that the idea of confusing a placebo response with developing real feelings is an intriguing notion.  He also thinks that some of the things that he referred to and I asked him about would not be picked up easily by someone who is not a specialist.  Therefore for the conventional spectator who does not have this specialist knowledge, it will not be received as preposterous or fictional, as a figment of the imagination.  People might recognise that the doctor should not really be that close to people and talking about their love life but other than that it was fun.

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. (Arlington VA, American Psychiatric Association, 2013)
Grassby, Paul, interviewed by Daniel Meyer-Dinkgräfe, unpublished, 14 October 2013.
Lappin, Graham, interviewed by Daniel Meyer-Dinkgräfe, unpublished, 14 October 2013.
Macfadden, Wayne, interviewed by Daniel Meyer-Dinkgräfe, unpublished, 17 October 2013. 
Prebble, Lucy, The Effect (London: Methuen Drama, 2012)
Shepherd-Barr, Kirsten, Science of Stage. From Doctor Faustus to Copenhagen (Princeton: Princeton University Press, 2012)7

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