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Research on the sick person


the course of history, the opinions have greatly varied when the time came to include the sick or the vulnerable in clinical research, especially when the prospects of benefits for the patients were remote. The ambiguous moral situation that results has been capture in the following quotes:

A fundamental moral paradox

The experimentation of new drugs on man is morally necessary, but necessarily immoral.

Jean Bernard, first President of the French National Ethics Committee, 19072006

We should not perform experiments susceptible to harm the individual.

The principle of medical and surgical morality, therefore, consists in never performing on man an experiment which might be harmful to him to any extent, even though the result highly advantageous to science, i.e., to the health of others.
Introduction to the Study of experimental Medicine, 1865
Claude Bernard 1813-1878

About Vulnerability


Recruiting vulnerable individuals in clinical trials creates a number of challenges both for the investigator/clinician and the research subject as well as special responsibilities for the health care provider/investigator Although individuals are not usually vulnerable at all times or in all aspects of their lives, they may be especially vulnerable in certain aspects exacerbated by the research context

Disease itself may be cause of vulnerability

The adult with early stage colon cancer, however, may or may not be vulnerable; that individual is a potentially vulnerable subject. [] The colon cancer patient may be psychologically unable to process information adequately or may be so emotionally impaired as to be unable to make his or her own research decisions. [] Frank vulnerability comes from objectives barriers to independence.
DeRenzo, EG, Moss, J., Writing clinical research protocols: ethical considerations , Academic Press, 2006, 67.

Defining vulnerability

There exist a number of definitions of vulnerability. Some well known, some less well known. The issue here is not to try and find the best one, but to satisfy ourselves about what vulnerability means and above all, try to reflect about what are the particular consequences that result from working with vulnerable patients, from an ethical perspective, and from a research ethics committee perspective.

Defining vulnerability

Definitions of vulnerability may be inward looking or they may be outward looking. These are somewhat arbitrary categories that I introduce. For example, being vulnerable may be equivalent to being fragile, inward looking, or to being unable to protect oneself, outward looking

Informed consent may not protect the vulnerable

In general, we identify as vulnerable those who are relatively (or absolutely) incapable of protecting their own interests. More formally, they have insufficient power, prowess, intelligence, resources, strength, or other needed attributes to protect their own interests through negotiations for informed consent.

Levine, R.J., Ethics and Regulation of Clinical Research, New Haven, Yale University Press, 1988, 62.

Vulnerability as Incapacity to Protect ones interests

Vulnerability can be broadly defined as the inability to protect ones interests. In relation to medical research, vulnerable individuals or populations are at increased risk of being harmed by research due to a decreased capacity to protect their personal interests.
Ballantyne, A., Rogers, W., Vulnerability and Protection in Human Research, Harvard Health Policy Review, 8 (1), 2007, 30.

Outward looking definition

These definitions are reminding us of an important value in our western culture, that of autonomy, literally the capacity to decide for ourselves, to lay out our own norms. This has been an important feature of the ethics of research over the last 30 years or so, reinforced in the Belmont Report from the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1974-1978) that came up with a set of guiding principles: autonomy, beneficence, and justice.

A word about principles

Principles are no doubt an important part of ethics, but far from being its central part. They represent accumulated positive experience and are useful considerations to incorporate in our deliberations. But they do not point out to solutions. Other aspects of ethics and morality are more essential. Suffice for now to insist on the centrality of an accurate perception of appropriate salient features of situations, informed by knowledge and accumulated experience.

Responsibility is for the fragile, the vulnerable

Any active responsibility starts with the question: What will happen to him if I do not take care of him. The more the answer is obscure, the more clearly it is presenting itself. Fear that is an essential part of Hans Jonas 1903 - 1993 responsibility is not the one that council us not to act, but rather the one that The Imperative of Responsibility, The University of Chicago Press, 1985. invites us to act.

Responsibility is for the fragile, the vulnerable

This fear that we are aiming at is the fear for the object of responsibility. It is an object that is fundamentally fragile for which it is possible to fear something.

Hans Jonas 1903 - 1993

The Imperative of Responsibility, The University of Chicago Press, 1985.

Inward looking definition

Jonas definition gets to the heart of the problem faced when dealing with recruitment of seriously ill patients, that is that they are fragile and they may die, they are essentially vulnerable as they may perish. And that we, all of us, have a responsibility to protect and promote the fragile, the vulnerable. And both the risks and the absence or low probability of benefits that are associated with phase 0 and phase 1 cancer trials do exacerbate the vulnerable status of the patient.

Domains of Vulnerability
Domain Description

(i) communicative vulnerability (ii) institutional vulnerability (iii) deferential vulnerability (iv) medical vulnerability

represented by participants impaired in their ability to communicate because of distressing symptoms; referred to participants who existed under the authority of othersfor example, in hospital; which included participants who were subject to the informal authority or the independent interests of others; which referred to participants with distressing medical conditions; and

(v) social which included participants considered to belong to J Koffman, M Morgan, P Edmonds, et al., Vulnerability in Palliative Care Research : Findings from a vulnerability an undervalued social group
Qualitative Study of Black Caribbean and White British Patients with Advanced Cancer, J Med Ethics 2009 35: 440-444

Vulnerabilities can be multiple (individuals might experience more than one of these vulnerabilities). It is sensitive to context, individuals may be vulnerable in one situation but not in another.

What policies say

Vulnerable Subjects - ICH

Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.

Ref: ICH E6 Guideline for Good Clinical Practices

CIOMS Guidelines

Special justification is required for inviting vulnerable individuals to serve as research subjects and, if they are selected, the means of protecting their rights and welfare must be strictly applied

Guideline 13: Research Involving Vulnerable Persons, International Ethical Guidelines for Biomedical Research Involving Human Subjects, Council for International Organizations of Medical Sciences (CIOMS) and World Health Organization (WHO) Geneva, Switzerland, 2002

Enrolling vulnerable patients

When vulnerability meets patients

Seriously ill individuals are often included in research because they or their physicians believe it is the best alternative to standard treatment. In these circumstances it can be difficult for prospective participants to weigh the risks and potential benefits associated with the research. Because of the absence of efficient standard treatment, cancer patients are often willing to accept risks of treatment that other patients would not.

Harris Interactive, New Survey Shows Public Perception of Opportunity to Participate in Clinical Trials Has Decreased Slightly From Last Year, Healthcare News 5(6) June 27, 2005.

Would consider participating in clinical research study

If I had a terminal illness If I thought the drug might cure me If there were no other medical options available to me If I knew there were no risks involved If I thought the drug/treatment would help me If the treatment were free of charge to me If my doctor recommended it If I received money for participating If I knew the risks associated with the treatment If I thought the drug/treatment would help someone else in future If it were convenient for me to participate If the location were convenient for me

% 2004 72 71 67 67 57 64 54 56 49 NA 53 54

% 2005 72 67 66 61 61 53 47 46 45 45 43 43

If there were minimal side effects associated with the treatment

If I knew I would receive an active treatment, not a placebo If I knew someone else who had the condition being studied

37 NA

33 30

Why do patients participate?

Not wanting to give up, to help other cancer patients, for their family and to have someone to talk to Patients in early anticancer trials will take part because of the intense support offered

Cox and McGarry. Eur J Cancer Care 12: 114, 2000

Why do patients participate?

therapeutic misconception

participants believe that clinical trials provide individualized treatment and direct benefit to subjects 43% of oncologists enrolled patientsto make sure they got state-of-the-art treatment
Lo and Guerin, Cancer Clinical Trials: Proactive Strategies, 2007.


patients with advanced cancer are faced with inducements that may that may sway their judgment of risk-benefit ratio. Should such patients be treated as vulnerable research subjects necessitating extraordinary supervision by third-parties? (Lipsett, JAMA 1982, 942).

Lipsett answered that every patient entering such a therapeutic trial is vulnerable by virtue of the disease state and the unique opportunity to receive a promising drug, but he maintained that the problem could be and was being overcome by painstaking consultation and preparation involving families, IRBs, third-party consultation and the like.
Ref: Veatch, Medical Ethics, 1997

Phases of Study
Phas e 0 Intent of Trial A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. It helps understand where the drug goes, and what is the interaction with the body. Drug development companies carry out Phase 0 studies to rank drug candidates in order to decide which has the best pharmacokinetic parameters in humans to take forward into further development. They enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data. Questions have been raised by experts about whether Phase 0 trials are useful, ethically acceptable, feasible, speed up the drug development process or save money, and Typical size of Trial 10-15 patients

Phases of Study
Phase I Intent of Trial Typical size of Trial Safety and defining short-term toxicities and 20 to 80 patients side effects. Determining maximal tolerated dose for Phase II efficacy studies and clinical pharmacology of dosing, including pharmacokinetics and pharmacodynamics. Collecting anecdotal clinical antitumor activity. Efficacy. Seeing if experimental agent(s) or combinations of experimental and proven agents have antitumor activity. Additional assessments of toxicities and side effects. Effectiveness. Comparing, usually in a randomized controlled trial, experimental agent(s) or combinations of experimental and proven agents with existing standard treatment(s) or, if no treatment(s), placebo to assess antitumor activity and side effects. 100 to 300 patients



More than 400 patients

New drug development timeline.

Eliopoulos H et al. Clin Cancer Res 2008;14:3683-3688

2008 by American Association for Cancer Research

Ethical Issues in Phase 0 Trials

Early determination whether a new drug is good candidate for further trials Subclinical dosage means no benefit can be gain TGN1412 trial in London shows small dosage may have unexpected catastrophic results Patients in desperate situation will do anything to help themselves and others, compromising the independence of consent

Ethical issues in phase 1 oncology trials

Because one of the end points of phase one oncology trials is toxicity, this is one area where voluntary volunteers give their place to affected individuals in phase 1 trials. There are three primary ethical concerns associated with phase 1 trials

Ethical issues in phase 1 oncology trials

1- The risk to benefit ratio is inherently unfavourable for research subjects 2- They enroll patients whose ability to provide valid informed consent may be compromised, and 3- They may take advantage of vulnerable subjects. In some of these studies, any benefit to the subject is, at best, highly unlikely. Subjects may experience a decline in health status from their participation, no improvements in terms of quality of life, or only a short prolongation of life.

Abdoler, E., et al., The Ethics of Phase 0 Oncology Trials, Clinical Cancer Research, 14 (2008, 3692-3.

The role of the REC in protecting the vulnerable

First protections for the vulnerable

After the atrocities from the Second World War, the Nuremberg Code was developed to ensure that the individual interests would prevail over the social interests and the interests of science itself. The Nuremberg Code of 1947 demanded:

qualified researchers use appropriate research designs That the research project had a favorable risk/benefit ratio That research subjects participate freely and be able to stop at any time

Additional protections

Recognizing the shortcomings of the Nuremberg Code, the Helsinki Declaration in 1964 brought additional protections:
The well-being of the subject should take precedence over the interests of science and society Consent should be in writing Use caution if participant is in dependent relationship with researcher Limited use of placebo Greater access to benefit The first revision of the Declaration in 1975 introduced the concept of oversight by an 'independent committee' (Article I.2) which later became the research ethics committee

Protecting the Vulnerable

Ultimately, the IRB and IEC bodies determine how vulnerable, if at all, a proposed subject population is and what protections will be required. Nonetheless, it is the investigator's responsibility to evaluate and define clearly the expected degree of vulnerability, justify the involvement of subjects with such characteristics, and build into study design any additional protections that might be needed.
DeRenzo, EG, Moss, J., Writing clinical research protocols: ethical considerations , Academic Press, 2006, 67.

The ethics committee must ensure that

The science is sound Fair selection of subjects The risks are minimized The benefits are maximized The research subjects are accurately informed and understand well it is research and what is the likeliness of benefits. They should be informed of alternatives to research. May be a case to involve family or significant independent others if capacity for understanding compromised The financial conflicts of interests are declared and do not interfere with subject protection

Ethics Committees can play a significant role in reducing medical vulnerability

Research ethics committees should satisfy themselves that the nature, magnitude, and probability of the risks and benefits of the research have been identified as clearly and as accurately as possible. They have a role both in considering circumstances in which terminally ill persons are appropriately excluded from research because they are a vulnerable group, and in providing persons who have no therapeutic alternatives the opportunity to receive the possible benefits of experimental interventions.

Ethics committees can play a significant role in reducing medical vulnerability

Special attention should be paid to the consent process, both in terms of the accuracy of the information to be provided and the manner in which consent is sought.

Understanding of informed consent

Questions might be asked to the subject to ensure appropriate understanding of consent process: 1- Can you tell me what will happen if you decide to be in this study? 2- Will being part in this study help you? 3- Can anything bad happen to you if you are part of this study? 4- Can you decide not to be part of or stop being part in this study? Silverman, H., Annals of Intensive Care, 2011, 1 (8)

Risk levels and essential safeguards for research studies involving critically ill patients Risk level and Proposed safeguards Level I: Procedures do not involve greater than minimal risk for any research. A written plan describing methods to assess decision making capacity If subjects do not have capacity to provide consent, then: Proxy consent; A process to respect assent and dissent of the subjects; A process to obtain re-consent from the subjects if and when subjects regain capacity Level II: Procedures of the research involve greater than minimal risk and offer the prospect of direct benefits. Level I safeguards Participation monitor: availability of an independent person to monitor the subject's involvement in the study, e.g., the subject's legal authorized representative.

Risk levels and essential safeguards for research studies involving critically ill patients Risk level and Proposed safeguards Level III: Procedures of the research do not involve greater than a minor increment above minimal risk and do not offer the prospect of direct benefits. Level I and II safeguards Necessity requirement Subject condition requirement Level IV: Procedures of the research involve greater than minimal risk and do not offer the prospect of direct benefits. Level I, II, and III safeguards Independent consent monitor Evidence of the subject's preferences and interests. Silverman, H., Annals of Intensive Care 2011 1:8


Cancer clinical trials are important to move toward effective treatments, but raise risks and possibilities of misunderstanding between clinician/researcher and patients Research ethics committees have a special responsibility to help identify vulnerable patients and try to minimize risks and ensure patients/subjects understand the nature of their involvement in research and the limitations in terms of potential benefits.

Thank you!