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RESEARCH INVULNERABLE
POPULATION:
RESEARCH INONCOLOGIC PATIENTS
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Research on the sick person
In 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 patientswere remote.
The ambiguous moral situation that results has
been capture in the following quotes:
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A fundamental moral paradox
The
experimentation
of new drugs onman is morally
necessary, but
necessarilyimmoral.
Jean Bernard, first
President of the French
National Ethics
Committee, 19072006
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e s ou no per ormexperiments susceptible to harm
the individual.The principle of medicaland 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 ofexperimental Medicine, 1865 Claude Bernard 1813-1878
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About Vulnerability
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Introduction
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 forthe 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
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Disease itself may be cause of
vulnerability
The adult with early stage colon cancer, however,may or may not be vulnerable; that individual is apotentially vulnerable subject. [] The colon cancerpatient may be psychologically unable to process
information adequately or may be so emotionallyimpaired as to be unable to make his or her ownresearch decisions. [] Frank vulnerability comesfrom objectives barriers to independence.
DeRenzo, EG, Moss, J., Writing clinical research protocols: ethicalconsiderations, Academic Press, 2006, 67.
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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 bestone, 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.
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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
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Informed consent may not protect
the vulnerable
In general, we identify as vulnerable thosewho are relatively (or absolutely) incapable ofprotecting their own interests. More formally,
they have insufficient power, prowess,intelligence, resources, strength, or otherneeded attributes to protect their owninterests through negotiations for informedconsent.
Levine, R.J., Ethics and Regulation of Clinical Research, NewHaven, Yale University Press, 1988, 62.
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Vulnerability as Incapacity to Protect ones
interests
Vulnerability can be broadly defined as theinability to protect ones interests. In relation to
medical research, vulnerable individuals orpopulations are at increased risk of beingharmed by research due to a decreasedcapacity to protect their personal interests.
Ballantyne, A., Rogers, W., Vulnerability and Protection in HumanResearch, Harvard Health Policy Review, 8 (1), 2007, 30.
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Outward looking definition
These definitions are reminding us of an importantvalue in our western culture, that of autonomy,literally the capacity to decide for ourselves, to layout our own norms.
This has been an important feature of the ethics ofresearch over the last 30 years or so, reinforced inthe Belmont Report from the National Commissionfor 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.
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A word about principles
Principles are no doubt an important part ofethics, but far from being its central part. Theyrepresent accumulated positive experienceand are useful considerations to incorporate inour deliberations. But they do not point out tosolutions.
Other aspects of ethics and morality are more
essential. Suffice for now to insist on thecentrality of an accurate perception ofappropriate salient features of situations,informed by knowledge and accumulated
experience.
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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 ofresponsibility is not the one
that council us not to act,
but rather the one that
invites us to act.
Hans Jonas 1903 - 1993
The Imperative of Responsibility, The University of Chicago Press, 1985.
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Responsibility is for the fragile, the
vulnerable
This fear that we are
aiming at is the fear
for the object of
responsibility. It isan object that is
fundamentally
fragile for which it is
possible to fearsomething.
Hans Jonas 1903 - 1993
The Imperative of Responsibility, The University of Chicago Press, 1985.
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Inward looking definition
Jonas definition gets to the heart of theproblem faced when dealing with recruitmentof seriously ill patients, that is that they arefragile and they may die, they are essentiallyvulnerable as they may perish. And that we, allof us, have a responsibility to protect andpromote the fragile, the vulnerable.
And both the risks and the absence or lowprobability of benefits that are associated withphase 0 and phase 1 cancer trials doexacerbate the vulnerable status of the patient.
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Domains of Vulnerability
Domain Description
(i)
communicative
vulnerability
represented by participants impaired in their ability
to communicate because of distressing symptoms;
(ii) institutionalvulnerability
referred to participants who existed under theauthority of othersfor example, in hospital;
(iii) deferential
vulnerability
which included participants who were subject to the
informal authority or the independent interests of
others;
(iv) medicalvulnerability
which referred to participants with distressingmedical conditions; and
(v) social
vulnerability
which included participants considered to belong to
an undervalued social groupJ Koffman, M Morgan, P Edmonds, et al., Vulnerability in Palliative Care Research : Findings from aQualitative Study of Black Caribbean and White British Patients with Advanced Cancer, J Med
Ethics 2009 35: 440-444
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Vulnerabilities can bemultiple(individualsmight experience morethan one of thesevulnerabilities).
It is sensitive to
context, individuals maybe vulnerable in onesituation but not inanother.
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What policies say
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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
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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 bestrictly 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
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Enrolling vulnerable patients
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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 bedifficult for prospective participants to
weigh the risks and potential benefits
associated with the research.
Because of the absence of efficientstandard treatment, cancer patients
are often willing to accept risks of
treatment that other patients would
not.
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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.
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Would consider participating in clinical research
study
% 2004 % 2005
If I had a terminal illness 72 72
If I thought the drug might cure me 71 67
If there were no other medical options available to me 67 66
If I knew there were no risks involved 67 61
If I thought the drug/treatment would help me 57 61
If the treatment were free of charge to me 64 53
If my doctor recommended it 54 47If I received money for participating 56 46
If I knew the risks associated with the treatment 49 45
If I thought the drug/treatment would help someone else in
future
NA 45
If it were convenient for me to participate 53 43
If the location were convenient for me 54 43
If there were minimal side effects associated with the
treatment
48 43
If I knew I would receive an active treatment, not a placebo 37 33
If I knew someone else who had the condition being studied NA 30
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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 partbecause of the intense support offered
Cox and McGarry. Eur J Cancer Care 12: 114, 2000
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Why do patients participate?
therapeutic misconception
many participants believe that clinical trials
provide individualized treatment and direct
benefit to subjects43% of oncologists enrolled patientsto make
sure they got state-of-the-art treatment
Lo and Guerin, Cancer Clinical Trials: Proactive Strategies, 2007.
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Similarly, patients with advanced cancer are facedwith inducements that may that may sway their
judgment of risk-benefit ratio. Should such patients betreated as vulnerable research subjects necessitatingextraordinary supervision by third-parties? (Lipsett,JAMA 1982, 942).
Lipsett answered that every patient entering such atherapeutic trial is vulnerable by virtue of the diseasestate and the unique opportunity to receive apromising drug, but he maintained that the problemcould be and was being overcome by painstakingconsultation and preparation involving families, IRBs,
third-party consultation and the like.
Ref: Veatch, Medical Ethics, 1997
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Phases of Study
Phas
e
Intent of Trial Typical size of Trial
0 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 isthe 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-godecisions 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 drugdevelo ment rocess or save mone and
10-15 patients
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Phases of Study
Phase Intent of Trial Typical size of Trial
I Safety and defining short-term toxicities and
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.
20 to 80 patients
II Efficacy. Seeing if experimental agent(s) or
combinations of experimental and proven
agents have antitumor activity. Additional
assessments of toxicities and side effects.
100 to 300 patients
III 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.
More than 400
patients
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New drug development timeline.
Eliopoulos H et al. Clin Cancer Res 2008;14:3683-3688
2008 by American Association for Cancer Research
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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 anythingto help themselves and others, compromising
the independence of consent
Ethi l i i h 1 l
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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
Ethi l i i h 1 l
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Ethical issues in phase 1 oncology
trials
1- The risk to benefit ratio is inherently unfavourablefor research subjects
2- They enroll patients whose ability to provide validinformed 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 adecline in health status from their participation, noimprovements in terms of quality of life, or only a short
prolongation of life.
Abdoler, E., et al., The Ethics of Phase 0 OncologyTrials, Clinical Cancer Research, 14 (2008, 3692-3.
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The role of the REC in protecting the
vulnerable
Fi t t ti f th
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First protections for the
vulnerable
After the atrocities from the Second WorldWar, the Nuremberg Code was developed toensure that the individual interests wouldprevail over the social interests and theinterests of science itself. The NurembergCode of 1947 demanded:
That qualified researchers use appropriateresearch designs
That the research project had a favorablerisk/benefit ratio
That research subjects participate freely and beable to stop at any time
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Additional protections
Recognizing the shortcomings of the NurembergCode, the Helsinki Declaration in 1964 broughtadditional protections: The well-being of the subject should take
precedence over the interests of science andsociety
Consent should be in writing
Use caution if participant is in dependentrelationship with researcher
Limited use of placebo Greater access to benefit
The first revision of the Declaration in 1975 introducedthe concept of oversight by an 'independentcommittee' (Article I.2) which later became the
research ethics committee
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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'sresponsibility to evaluate and define clearly the
expected degree of vulnerability,justify the
involvement of subjects with such
characteristics, and build into study design anyadditional protections that might be needed.
DeRenzo, EG, Moss, J., Writing clinical research protocols: ethical
considerations, Academic Press, 2006, 67.
Th thi itt t
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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 andunderstand well it is research and what is thelikeliness of benefits. They should be informed ofalternatives to research. May be a case to involve
family or significant independent others if capacity forunderstanding compromised
The financial conflicts of interests are declared and donot interfere with subject protection
Ethics Committees can play a
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Ethics Committees can play asignificant 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 becausethey are a vulnerable group, and in providing
persons who have no therapeutic alternatives the
opportunity to receive the possible benefits of
experimental interventions.
cs comm ees can p ay a
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cs comm ees can p ay asignificant role in reducing medical
vulnerability
Special attention should be paid to the
consent process, both in terms of the
accuracy of the information to beprovided and the manner in which
consent is sought.
Understanding of informed
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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 youdecide to be in this study?
2- Will being part in this study help you?
3- Can anything bad happen to you if you arepart 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)
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Risk levels and essential safeguards for research studies involving critically ill
patientsRisk 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.
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Risk levels and essential safeguards for research studies involving critically
ill patients
Risk level andProposed 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 anddo 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 Care2011 1:8
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Conclusion
Cancer clinical trials are important to movetoward effective treatments, but raise risks andpossibilities of misunderstanding betweenclinician/researcher and patients
Research ethics committees have a specialresponsibility to help identify vulnerablepatients and try to minimize risks and ensure
patients/subjects understand the nature oftheir involvement in research and thelimitations in terms of potential benefits.
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Thank you!