6 Research Vulnerable Populations Research Oncologic Patients

8/13/2019 6 Research Vulnerable Populations Research Oncologic Patients

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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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6 Research Vulnerable Populations Research Oncologic Patients

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