#15649 - Human Subjects Research I - Medical Law

Introduction

Basic issue is how to balance the competing interests of society and the individual research subject. This stands as a good example of the conflict between deontological and teleological reasoning.

A strict utilitarian approach would conclude that conducting experiments on a small number of people with or without their consent will be justifiable if the benefit to the rest of society is greater. For example, the discovery of smallpox vaccine by Edward Jenner. In contrast, a strict deontological approach would condemn any course of action that disregarded the wellbeing of individual research subjects, regardless of the benefits to the rest of society. Jonas has gone as far to say that research on humans involves treating subjects as ‘things’ and that we should not permit this, regardless of the consequences it might have for the people suffering from potentially curable diseases. In other words, erosion of morals > scientific progress.

Both extremes are unattractive. Bottom line is: we all benefit from living in a society which drugs and other treatments have been properly tested. It might therefore be argued that we are under a moral obligation to incur some inconvenience or slightly increased risk to our health by participating in medical research. If we wish to benefit from experiments on humans, but are not actually willing to take part, could we be said to be ‘free-riding’?

It is also important to remember that a third party might also be interested: that of the researcher, and the economic incentives they receive for devising, carrying out and publishing research. This may incentivise cutting corners at the cost of others’ interests. Arguably boiling down to a utilitarian perspective: why make drugs for sick people who cannot afford them?

i. The position under international guidelines

Under the Helsinki Declaration, in paragraph 5, it is said that “In medical research on human subjects, considerations related to the wellbeing of the human subject should take precedence over the interests of science and society”. As a general remark about the obligations of the research community, the health care system, society or indeed of the world community, Harris finds that this remark is not sustainable. In particular, the rights and interests of research subjects are surely not served by privileging them at the expense of the rights and interests of those who will benefit from research.

Both these groups are potentially vulnerable, neither is obviously prima facie more vulnerable or deserving of special protection. If anything, the research subjects are part of the larger group which will ultimately benefit from research. Harris suggests to say that the interests of the subject must take precedence over those of others, if it means anything, must be understood as a way of reasserting that a researcher’s narrowly conceived professional interests must not have primacy over the human rights of research subjects.

A. The dimensions of human subjects research

a) What is ‘research’?

Research is generally any form of study undertaken to produce generalisable results. Clinical trials will often give rise to the doctor/patient duty of care. Great deals of medical research are carried out without making contact with patients e.g. research on health data and biomaterials as opposed to persons. Major difficulties would be posed if patients had to give informed consent to the use of information from things like medical notes taken by their doctors. Ideally, the patient’s agreement to use of the information gathered during treatment should be sought, but if it would be impossible to obtain consent, then there are times, when anonymised data can be used for research purposes. The issues with this have been discussed previously and will also be briefly considered below.

Compare this with innovative treatments/therapy, which may occur outside a doctor/patient relationship. The Helsinki Declaration endorses the use of unproven treatment where no other option exists. These are intended to achieve results for certain individual patients, and not generally for the purposes of creating generalisable knowledge. The desire of a desperately ill patient to try anything is understandable, but at the same time, patients may overestimate the likelihood of success and underestimate the risks of untested treatments. Expanded access to yet unapproved medicines may represent a clash between autonomy and informed consent. Accordingly, the fact that treatment is untested may be a material fact, non-disclosure of which might trigger negligence.

b) What are the stages of research?

After satisfactory evidence from animal trials has been gathered, there are usually three phases of trials on humans. Phase 1 trials involve a small number of healthy volunteers, who are given the drug so that researchers can study its toxicity, and the way in which it is absorbed. Phase 2 trials involve giving the drug to a group of people suffering from the condition it is intended to treat in order to evaluate its effectiveness, and discover if it has any side effects. Phase 3 trials involve monitoring a larger group of subjects who take the medicine under supervision for a longer period of time (here, typically involve RCTs). Phase 4 trials involve looking at how the drug works in the real world, after distribution to the market, and will include patients normally excluded from the previous trials e.g. pregnant women and children.

c) Distinction between therapeutic and non-therapeutic research

Phase 1 trials are normally non-therapeutic, whereas Phase 2 and 3 are therapeutic. For certain drugs, it will be unethical to start on Phase 1 e.g. chemo drugs. The possible dangers of Phase 1 trials was illustrated in 2006 re the trial of TGN1412.

The therapeutic and non-therapeutic distinction may be difficult to draw at times. As Levine explains, every trial has some components which are non-therapeutic. The principal consequences of labelling research as therapeutic is to weaken the protection available to vulnerable subjects. Patients who lack capacity can be enrolled in a research trial more easily if the trial can be described as ‘therapeutic’ even if it contains elements that are quite self-evidently non-therapeutic. Verdun-Jones and Weisstub are very critical of things being labelled therapeutic when the benefits are merely ‘possible’, ‘hypothetical’ or ‘speculative’.

There is also the issue of saying something is therapeutic when research is being conducted on its efficacy - if it was therapeutic, then research wouldn't need to be done on it. Randomised control trials (RCTs) give rise to further issues in this context: in a placebo controlled RCT, there may be a 50% chance the patient will receive no treatment at all. Is such a trial ‘therapeutic’?

i. Component risk analysis - an alternative approach

A better approach outlined by Weijer is to analyse research in terms of its therapeutic and research components. Therapeutic components are the activities researchers do which they know may prove of therapeutic use to the particular individual, and which could be undertaken lawfully and ethically by a doctor treating a patient. In contrast, research components are the activities that are done without any likelihood of benefit for the patient. These activities would not occur save for the fact that the doctor is trying to produce generalisable knowledge. What appears to be a singular research programme will often consist of a mix of components.

The value of component risk analysis lies in the fact it enables the activities a researcher carries out with therapeutic warrant to be analysed separately from the thing the researcher does that are solely intended to serve the public. The risks associated with the former (i.e. therapeutic) are not special (researcher only needs to show risks are compatible with normal clinical standards of care, and that they have observed the principle of clinical equipoise), but the risks associated with the latter (non-therapeutic) are. Here, the researcher uses the patient in order to serve a wider population and hence special mechanisms of oversight as warranted to ensure the patient is not exploited or exposed to unnecessary risk. In short, the value of component risk analysis is that it enables the incremental risk associated with the search for scientific knowledge to be distinguished and regulated differently from risks associated with attempts to improve the patient’s personal situation.

The conventional classification of therapeutic and non-therapeutic research distinguishes risk in a less than sophisticated way by aggregating associated risks (both clinical and research) into a single net calculation. As might be expected, most research related deaths occur in situations where research is classified as having ‘direct benefit for the subjects’ (i.e. therapeutic research) because aggregate risk analysis does not pressure researchers to minimise research risks. Aggregate risk analysis also tends to preclude research when the patient suffers from a condition which there is no effective therapy, yet the research risks are minimal.

B. The regulation of human subjects research

As a result of the Nuremberg trials, the court at Nuremberg set out a Code to govern the future conduct of medical research in order to protect the subjects’ interest. Although this code has symbolic value, its impact on the medical profession has been limited since most of it was drafted on the basis of addressing the abuses...