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.
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’.
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.
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.
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.
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.
Conclusion
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.
References
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
