The Ethics Of Phase 1 Research In Patients

ctionA comparison to existing treatments is also
Phase 1 trials are the gatekeeper of clinical researchmisleading. Many Phase 1 patients have exhausted
as they are often the first time a potential new drugtreatment options so marketed treatments are not a
treatment enters humans ( First-in-Man or FIM trials).valid comparison. In addition drugs on the marketplace
In the past FIM trials usually enrolled between 20 andare often registered on the basis of different clinical
80 healthy volunteers carefully screened for theoutcomes than those being measured in clinical trials.
absence of disease and in part paid for trialFinally as 90% of drugs fail in the development
participation. However, this is no longer the case. Dueprocess, the use of a benchmark to existing drugs
to recent concerns over drug safety — forsets a very high barrier.
example the Northwick Park experience withInstead perhaps it is more valid to consider the risks
TGN1412 causing serious adverse reactions in healthyand benefits of enrolling in a clinical trial against the
volunteers - and with the advance of medical scienceuse of off label medication by doctors and patients.
leading to the development of treatments withIn this case the treatment population is the same
greater specificity Phase 1 research now increasingly— both patients enrolling in clinical trials and
considers patients.those wanting to use off label treatments have
The involvement of patients brings a new dimensionrejected palliative care in the first instance. In addition
to research; patients can conceivability benefit fromof label use outcomes are often expressed in terms
clinical trials and in considering entering a clinical trialof anecdotal outcomes rather than registration
both the patients and the attending doctor mustendpoints. The problem is that this data is hard to
consider the alternatives of treatment. For this latterobtain. However, what is known in the field of
reason, perhaps, many clinical trials involving patientsoncology is that approximately 4% of patients have
only consider the terminally ill as candidates for themeaningful clinical endpoint outcomes in Phase 1 trials
clinical trials. The perception of benefit also means(Joffe & Miller, 2006). This contrasts with the
that patients in Phase 1 clinical trials are not paid.reported rate of toxicity death rates of 0.5%
There are also ethical considerations when considering(Addoler, Taylor, & Wendler, 2008). These figures
the enrolment of patients. In the conduct of medicalargue against the proposal that Phase 1 clinical trials in
care the free will or autonomy of the patient is seenpatients cause harm, as in the population that enrol in
as prime. Failure to respect the wish of patients inclinical trials have risks and benefits comparable to off
deciding their treatment is seen as morally wrong,label use of existing drugs (Joffe & Miller, 2006).
and in most countries subject to legal sanction.A second argument for the fact that patients suffer
Coupled with the demands of autonomy, and inharms in Phase 1 clinical trials is that the usual
support of it, are the requirements to fully informoutcomes cannot measure harm, and that the harms
patients about the potential effects of treatmentare best expressed in terms of Quality of Life (Qol).
and the alternatives available. Balancing these rolesThe harm it is argues is a decline in Qol due to clinic
and responsibilities on the medical profession are thevisits and procedures. There is little data available on
requirements that doctors should do no harm andthis aspect, but what does exist suggests that many
also ensure the just use of resources. These ethicalpatients Qol is not changed by enrolment in a Phase 1
principles are enshrined in the ethical principles ofclinical trial as the majority of these trials are short in
deontology. In this school of ethical thought it is theduration (Addoler, Taylor, & Wendler, 2008).
intentions not the outcomes that determine morallyBased on these findings it is difficult to argue
acceptable behaviour. For example if you have actedconvincingly that the risks and benefit balance of
in a way that respected patient autonomy, and fullyPhase 1 clinical trials in patients are better or worse
informed them of the outcomes of choices, and thethan the alternatives, and therefore to argue that
patient has a bad outcome, you have still acted in atheir exclusion from Phase 1 trials can be justified on
morally acceptable manner. In contrast scientificthe trials cause harm.
research has a different ethical perspective. It is the2. Patients cannot provide a valid informed consent,
magnitude of the outcome that matters in Phase 1as they are not consenting for themselves but the
research in order to select a dose for a subsequentcollection of generalisable information.
trial or the determination of a toxic dose (Shamoo,The foundation to this objection is that patients do
2008). Another factor in the conduct of research isnot appreciate or understand that they are
that the results should be generalisable to aparticipating in clinical research, and do not receive or
population of patients in order to extrapolate theperceive the information they are given and
meaning of results. In this instance the intention is nottherefore informed consent is not valid.
to select a treatment for an individual patient. TheEmpirical studies cast doubt on this assertion
focus on the outcome of the clinical trial, and the(Addoler, Taylor, & Wendler, 2008). Interviews with
intention to gather generalisable information gives thepatients enrolling into clinical trials have shown that
ethics of clinical research — and Phase 1 clinicalthe majority of subjects do understand the nature of
research in particular — a so calledthe trial into which they are enrolling, albeit the
consequentialist approach. Consequentialist ethics areprimary motivation for enrolment was the hope of
concerned with the outcome of an action, rathersome benefit.
than the intention of the action. Perhaps the bestOf greater concern in the process of informed
known consquentialist approach is utilitarianismconsent is the issue of voluntariness. In other words
— acting in a way that leads to the benefit forthat the participation in a clinical trial stems from
the greatest number. Phase 1 research is often saidpressure from a physician whom is also acting as an
to be utilitarian in nature as it seeks generalisableinvestigator. There is some evidence that doctors
knowledge.over-estimate the chances of benefit from clinical
The deontological and consequentialist andtrials mostly unintentionally (Addoler, Taylor, &
approaches often lead to different definitions ofWendler, 2008). However, in interviews with patients,
what is morally correct and acceptable. Consider this.the role of physician advice in enrolling in trials
You are standing at a bus stop when a man comesappeared to be low.
up to you and says he is being chased by an axeOn the other hand the fact that patients cannot give
murderer. He says he is going to hide in the bushes tillinformed consent to enter into clinical trials also
the person passes and does so. A few minutes laterseems weak.
a man carrying an axe runs up and asks if you have3. Patients whom are terminally ill are vulnerable and
seen anybody, what do you do?so are liable to be manipulated.
As a consequentialist, you would say you sawThis argument is closely related to the other two
nobody as the consequences of your action wouldobjections, and suggests that as patients are unable
lead to murder.to assess risks and benefits and give full consent
As a deontologist in a strict sense you would say hethey are vulnerable to manipulation. This argument
is in the bushes as it is always morally wrong toalso does not stand up to empirical analysis. Studies
deceive anybody!have indicated that the population that enrol into
The conflict between the deontological approachesclinical trials are not economically or socially
of medical practice and the utilitarian perspective ofdisadvantaged (Addoler, Taylor, & Wendler, 2008).
clinical research in Phase 1 has lead some ethicists toFurthermore, other wishes of terminally ill patients are
conclude that it is not ethical to enrol patients inoften respected in terms of Advance Directives. So
Phase 1 studies. The foundation of this claim is thatit is hard to argue that the patients whom enrol in
as these are patients their care is paramount, andtrials are vulnerable.
patients cannot exercise autonomy in their choice asConclusions
1. Phase 1 clinical trials causes more harm to patientsThis review has made the argument that patients
than potential benefits.should be enrolled in Phase 1 clinical trials, as it
2. Patients cannot provide a valid informed consent,enrolment in a trial appears to do them no harm, and
as they are not consenting for themselves but thecould provide benefit no worse than other
collection of generalisable information.interventions. Arguments that these patients cannot
3. Patients whom are terminally ill are vulnerable andconsent, or are too vulnerable are not valid
so are liable to be manipulated.objections to patient enrolment.
Taking these factors in turn:This conclusion has some impact, for in many aspects
1. Phase 1 clinical trials causes more harm to patientsit argues that patients and healthy volunteers face
than potential benefits.identical ethical issues in their participation in Phase 1
This statement leads to another question —research. This begs the question, should we not pay
more harm that what or more benefit than what?patients for enrolling in Phase 1 research. It is hard to
Both the deontological and consequentialistargue against if we accept that the ethical dilemmas
approaches to medical ethics requires carefulare identical.
consideration of the risks and potential benefits of aWhat the review has highlighted is that there is a
medical intervention be it an operation or a clinical trial.genuine concern over the voluntary nature of
In making an assessment of the intervention it isconsent in clinical research in phase 1, and there may
usual to have some form of comparator. In Phase 1be a need to redefine the doctor patient relationship
clinical trials three methods have been used. The firstin circumstances where a physician is also an
is to compare it to the alternative of palliative careinvestigator. It may be a necessity to put in other
— particularly in cancer, but also inpatient safeguards such as other doctors or nurses
inflammatory diseases. The second way of comparingbesides the investigator obtaining the informed
risks and benefits is to look at the approved cancerconsent.
treatments and draw parallels with the currentlyBibliography
licensed medications available from the FDA or theAddoler, E., Taylor, H., & Wendler, D. (2008). The
European regulators. The third is to draw parallelsEthics of Phase 0 Oncology Trials. Clinical Cancer Rees
with the use of off label medications in cancer (Joffe, 14, 3962-3967.
& Miller, 2006).Joffe, S., & Miller, F. (2006). Rethinking the Risk
The use of a comparison to palliative care is not valid.Benefit for Phase 1 Cancer Trials. J Clin Oncol , 19,
The patients whom enter a Phase 1 clinical trial have2987-2990.
already rejected it as an option at the moment theyShamoo, A. (2008). The Myth of Equipose in Phase 1
enrol in a clinical trial. In addition they have notTrails.
rejected it in the future by enrolling in a trial.