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Empowerment of Terminally Ill
Research Subjects
Uniformed Services University of the Health Sciences
February 10, 2014
Lauren Solberg, JD, MTS
Assistant Professor,
Program in Bioethics, Law & Medical Professionalism
Department of Community Health & Family Medicine;
Departments of Aging and Geriatric Research & Psychiatry
Goals of This Session
Discuss perceptions of terminally ill persons
as vulnerable research subjects, present
Identify ways terminally ill individuals are
empowered under law to make clinical care
Describe how informed consent process,
other mechanisms can empower terminally ill
individuals in research context,
combat/counteract perceptions of vulnerability
What is “Terminally Ill”?
Terminally ill person – one who is
reasonably expected to die within a short
period of time from a particular disease or
Ronald Bayer et al., The Care of the Terminally Ill: Mortality and Economics,
309 NEJM 1490 (1983).
“Short period” not necessarily set period
Sometimes individual lives beyond
anticipated timeframe
Perceptions of Terminally Ill as
Vulnerable Research Population
Google “terminally ill research population”
(without quotes)
What results do you see?
Vulnerability Perceived
Regardless of Research Type?
Concerns about potential vulnerability in
biomedical research (i.e. clinical trials)
Also concerns about potential vulnerability
in social/behavioral research
Perception of Vulnerability of
Terminally Ill Based On…
Interpretation of federal regulations, other
Possibility of therapeutic misconception
Hope for survival
Potential diminished capacity for consent
– Either at the time of enrollment or at some point
during the study
Pressure from physicians (esp. those who may
also be researchers)
No right to unapproved drugs
How persuasive are each of these?
Some more so than others…
Let’s discuss!
Vulnerability Under the
IRBs that regularly review research
involving vulnerable populations (such as
children, pregnant women, prisoners, or
handicapped or mentally disabled
persons) should include one or more
people with knowledge/experience about
working with those populations
45 C.F.R. §46.111(a)(3); 21 C.F.R. §56.107(a); 32 C.F.R. §219.107(a)
Vulnerability Under the
Regulations (cont’d)
IRBs must ensure subject selection is
equitable – should be cognizant of
involvement of vulnerable populations
(such as children, prisoners, pregnant
women, handicapped, or mentally disabled
persons, or economically or educationally
disadvantaged persons)
45 C.F.R. §46.107(a)(3); 21 C.F.R. §56.111(a)(3); 32 C.F.R. §219.111(a)(3)
Vulnerability Under the
Regulations (cont’d)
When some/all subjects likely to be
vulnerable to coercion or undue influence
(such as children, prisoners, pregnant
women, handicapped, or mentally disabled
persons, or economically or educationally
disadvantaged persons), IRBs must
ensure additional safeguards have been
included in the study to protect rights and
welfare of these subjects
45 C.F.R. § 46.111(b); 21 C.F.R. §56.111(b); 32 C.F.R. §219.111(b)
The Belmont Report
Published 1979
Terminally ill listed among populations that
may be “incompetent”
Concern that comprehension may be
OHRP’s IRB Guidebook
Last updated in 1993
Chapter 6 – Special Classes of Subjects
Terminally ill considered vulnerable
population of research subjects
But should not be excluded from research
participation just because of their status
Vulnerable Under the Regs?
Terminally ill populations not specifically
mentioned in federal human subjects
research regulations as vulnerable
– In either Common Rule or FDA regulations
So decision that terminally ill people are
vulnerable subjects is based on local
IRB/researcher interpretation (perhaps in
conjunction with analysis of other sources)
– Other sources only advisory
Therapeutic Misconception
“Research subjects will assume (especially,
but not exclusively, in therapeutic research)
that decisions about their care are being
made solely with their benefit in mind.”
Appelbaum, P. S.; Roth, L. H.; Lidz, C. (1982). "The therapeutic
misconception: Informed consent in psychiatric research". International
Journal of Law and Psychiatry 5 (3–4): 319–329.
Subject’s false belief that study will provide
him/her with therapeutic benefit
Shira Bender et al. (2007). Access for the Terminally Ill to Experimental Medical
Innovations: A Three-Pronged Threat. AM J BIOETHICS, 7(10): 3-6.
Misunderstanding of Research =
But this can be said for anyone!
Not just limited to terminally ill individuals
Not even limited to people with “serious”
diseases or terminal diseases
– Appelbaum study shows therapeutic
misconception in participants in studies about
plantar warts, Sjogren’s syndrome
Paul S. Appelbaum, Charles W. Lidz, and Thomas Grisso, “Therapeutic Misconception in
Clinical Research: Frequency and Risk Factors,” IRB: Ethics & Human Research 26 No. 2
(2004): 1-8.
Hope for Survival
Terminally ill cancer patients tend to overestimate
survival time
Possible denial of poor prognosis, unrealistic
hope of survival
Unrealistic expectations about clinical trials,
potential benefits (different from therapeutic
Manish Agrawal & Mario Danis, End-of-life Care for Terminally Ill Participants in Clinical Research, 5 J.
Palliative Med. 729, 732-33 (2002).
BUT…studies report Phase I oncology study
participants hope their condition will improve, yet
still understand the study
Emily Abdoler et al., The Ethics of Phase 0 Oncology Trials, 14 CLIN. CANCER RES. 3692, 3694 (2008)
“Therapeutic Doublethink”
Doublethink – from Orwell’s 1984 - having
2 contradictory beliefs, accepting both of
Unrealistic optimism on part of patient
doesn’t mean he/she hasn’t accepted
terminal diagnosis
Beneficial for patients with cancer
– Psychological benefits
Therapeutic Doublethink: A Novel Concept to Ethically Justify Unrealistic Optimism in Patients with
Advanced Cancer; Irene Ying, University of Toronto, as presented at ASBH meeting, Oct. 2013
Judging Enrollment Decisions
In general, subjects who understand – and
demonstrate understanding of – the study’s
purpose(s), risks and benefits, etc. are permitted
to consent
– More about consent later!
Must subject’s decision to enroll be based on the
researcher’s stated purpose of the study?
– Can a subject enroll in a study for another reason?
– Should subjects enroll in a study only if they enroll
for the “right reasons” (i.e., study’s true purpose)?
– Is hope for survival a “wrong reason”?
Subject Compensation – A
“Right Reason”?
Ex: community-engaged research/CBPR
– Studies show motivation for enrolling is often the
compensation that is offered
Ex: FDA-regulated research
– FDA guidance says subject payment incentivizes
research participation, is not a benefit
So why question other reasons for enrolling
in research?
Capacity Concerns
10-40% of terminally ill patients experience
cognitive impairment in last months of life
Up to 85% of terminally ill patients
experience cognitive impairment in last days
of life
Clinical depression could affect capacity –
and 5-25% of terminally ill patients suffer
from depression
David Casarett, Ethical Considerations in End-of-Life Care and Research, 8 J.
Palliative Med. S-148,S-156 (2005).
Cognitive Impairment =
But this can be said for anyone!
< half of terminally ill patients experience
cognitive impairment in last months of life
So why consider the population as a whole
to be vulnerable?
– Instead: terminally ill people who are
cognitively impaired are vulnerable because
of limited ability to make decisions
– Not vulnerable because of terminally ill status
Inability to Make Voluntary
Not because of course of disease, but…
In clinical trials, unreasonable to expect people to
accept 50/50 chance of receiving placebo when
doing nothing = certain death
“True volunteer” would have reasonable alternative
to possibly receiving placebo in clinical trial
– Not offering experimental drugs outside of clinical
trial coerces people into studies that aren’t
necessarily in their best interests
Can autonomous choice be made if subject has no
idea if intervention will work?
Subject doesn’t need to know if intervention will
Subject just needs to understand limited
knowledge about intervention, resulting risk that
would be undertaken by enrolling
– Especially if study not designed to directly
benefit participant (i.e. Phase I study)
“Decision about what risks a competent person
takes in the face of death is fundamentally a
personal choice”
Udo Schüklenk & Christopher Lowry. (2009). Terminal Illness and Access to Phase 1
Experimental Agents, Surgeries and Devices: Reviewing the Ethical Arguments. BRIT
MED BULLETIN; 89: 7-22.
Physician Pressure to Participate
7% of Phase I oncology study subjects feel
moderate or significant pressure to participate
9% think patients in general (not just Phase Ieligible subjects) are subject to physician
pressures to participate
Emily Abdoler et al., The Ethics of Phase 0 Oncology Trials, 14 CLIN. CANCER RES. 3692, 3694 (2008).
BUT…these are small numbers
And COI regulations, IRB scrutiny of
recruitment procedures helps control this
Limited Access to
Unapproved Drugs
Clinical trials likely only way someone with
terminal illness will access investigational
– But not everyone is eligible
Access through expanded access (aka
“compassionate use”) possible
– But requirements are stringent for receiving
drug this way
U.S. v. Rutherford (1979)
Terminally ill cancer patients sued because
U.S. government prohibited sale of
unapproved drug (laetrile)
Court of Appeals, 10th circuit held terminally
ill patients exempt from FDA restrictions
SCOTUS reversed – FDCA does not provide
for exceptions to allow terminally ill to have
access to unapproved drugs
SCOTUS’ Reasoning
Pre-FDCA (1938) – Congress concerned
about people with fatal illnesses being
“shielded from fraudulent cures”
Irreversible consequences if conventional
therapy rejected in favor of unproven
Clinical testing ok under FDCA, unfettered
access is not
U.S. v. Rutherford, 442 U.S. 544 (1979)
Abigail Alliance v.
von Eschenbach
Abigail Burroughs’ dad sued FDA for
access to investigational drug being
studied in colon cancer patients
– She had head/neck cancer
Argued FDA should allow terminally ill to
access drugs after completing Phase I
investigation, before FDA approval
– Compassionate use – after Phase II (or later)
studies complete
Outcome of Abigail Alliance Case
2007 – U.S. Court of Appeals, D.C. held
there is no constitutional right to access to
drugs not yet approved by FDA
– 495 F.3d 695 (D.C. Cir. 2007)
SCOTUS refused to hear appeal
Did the court get it right?
Empowerment Under the Law
Statutes and Regulations
Court opinions
Right to Withhold/Withdraw
“It cannot be disputed that the Due Process
Clause protects an interest in life as well as
an interest in refusing life-sustaining medical
Cruzan v. MO Dep’t of Health, 497 U.S. 261
*Competent people have Due Process right
to refuse life-sustaining treatment
Minors Rights Under the Law
26 states plus DC allow minors 12+ to consent to
contraceptive services
All states plus DC allow all minors to receive STI
treatment without parental consent
32 states plus DC allow minors to consent to all
prenatal treatment
Abortion – varies (some parental consent, some
parental notification, 2 states allow all minors to
Oregon, Washington
OR Death with Dignity Act (1997)
WA Death with Dignity Act (2009)
Patients 18+, residents of OR/WA, can make own
health care decisions, diagnosed with terminal illness
(< 6 months to live), voluntarily stated wish to die
May voluntarily self-administer medication to end their
lives with drugs prescribed by physician for this
Accompanying regulations provide reporting
requirements, etc.
Patient Choice and Control at End of Life
Act, passed in 2013
Modeled after OR statute
First statute legalizing physician-assisted
suicide to be passed by legislature
OR initiative approved by 51.3% of voters,
WA initiative approved by 57.72% of
ASBH presentation, Legal update 2013: top 10 Legal Developments in Bioethics
Baxter v. MT, 224 P.3d 1211 (2009)
– No right to die under MT state constitution
– But assisted suicide not against MT public
– Consent exception under MT law could apply
to physicians assisting in suicide (no homicide
New Mexico
Morris v. Brandenberg (2014)
– State of New Mexico, Bernalillo County,
Second Judicial District
“This court cannot envision a right more
fundamental, more private or more integral
to the liberty, safety and happiness of a
New Mexican than the right of a
competent, terminally ill patient to choose
aid in dying.”
Some Statistics
OR – 2013 – 122 prescriptions written under Act
– Written by 62 different drs
63 deaths were from prescriptions written in 2013
– 71 people died, 8 from 2011, 2012 prescriptions
28 people died from other causes
Remaining 31, ingestion status currently unknown
– 7 died but cause unknown, status of remaining
24 unknown
***Most frequently stated end-of-life concern –
loss of autonomy
MI, 1997
Dignified Death Act (amendments since ‘97)
Patients diagnosed with “reduced life
expectancy” or their decision-makers, where
appropriate must be informed about:
– Recommended medical treatment and alternatives,
and advantages/disadvantages, risks of each
– Right to appoint someone to make health care
decisions for them in event of incapacity
– Right to make decision about receiving, continuing,
refusing, discontinuing treatment
– Right to palliative care
– Right to pain and symptom management
CA, 2009
Right to Know End of Life Options Act
When diagnosis of terminal illness made,
upon patient’s request, health care
provider must provide patient w/
comprehensive information and
counseling on end of life care options
Statute details information that must be
included – such as right to refuse/withdraw
treatment, right to pain management, etc.
NY, 2010
Palliative Care Information Act
Terminally ill patients (with
illness/condition reasonably expected to
cause death within 6 months) MUST be
offered information by health care provider
about palliative care, end of life options
Empowerment to Tweet!
Empowerment to Make Clinical
Should = empowerment to make decisions about
research participation
– Concerns about vulnerability of terminally ill not necessarily
strong arguments in favor of vulnerability
– Terminally ill can make decisions about
withdrawal/termination of medical care, PAS
– Should therefore be presumption that they are not vulnerable
– Could be rebuttable presumption based on particular
study, study population
And…We have a mandatory informed consent
process under federal regulations to combat
vulnerability concerns
Informed Consent Empowers
Research Subjects
By regulation, informed consent process is
– 8 required elements of consent
– 6 additional elements that shall be provided to
subjects where appropriate
Unless waiver granted by IRB, subjects
must explicitly consent to all aspects of
non-exempt research
8 Required Elements of Consent
Purpose of the research, description of procedures
involved, duration of participation (1)
Risks, benefits of participation (2,3)
Alternatives to participation, if any (4)
How confidentiality of data will be protected (5)
Compensation/treatment in event of injury
information (for > minimal risk studies) (6)
Statement that participation is voluntary,
withdrawal ok at any time (7)
Contact information for PI, IRB, other key study
team members (8)
6 Additional Elements
Statement that treatment/procedure may involve
currently unforeseeable risks
Circumstances under which PI may terminate
subject's participation without subject's consent
Additional costs to subject for participation
Consequences of decision to withdraw, procedures
for terminating participation
Statement that significant new findings which may
relate to subject's willingness to continue
participation will be provided to the subject
Approx. # of subjects participating in study
Criticisms of Informed Consent
Many criticisms detailed in July 2011 ANPRM
Consent forms too long, too detailed
Really protecting institutions, not participants
Easy to miss important info in consent forms
IRBs too rigid about requiring written consent
form where it may not be necessary
ANPRM includes number of possible ways to
overcome these issues
– http://www.gpo.gov/fdsys/pkg/FR-2011-07-26/pdf/2011-18792.pdf
Good Verbal Discussion Can
Help Compensate
Thorough discussion with potential
participants (not just vulnerable ones) can
help compensate for many of these issues
Especially important with potentially
vulnerable population to include this
component of consent process
Additional Consent Suggestions
Consider who best person from research team is
to consent participant
Discuss potential benefit(s) and potential lack of
benefit(s) to allow for voluntary decision-making
– Be sure that it is clear what subjects are giving up
in order to participate
Periodic reminders (at designated intervals) of
alternatives to participation
– Consent is ongoing process
– Even if no indication that subject may change
his/her mind
In Event of Incapacity…
Subjects may differ re: desire to participate
May wish to discontinue/not participate
– Reaching stage of incapacity = total loss of hope
May wish to participate/continue participation
– Hope of regaining capacity
– Belief that their families, research teams would
want them to continue
– Desire to contribute to research to benefit future
Manish Agrawal & Mario Danis, End-of-life Care for Terminally Ill Participants in Clinical
Research, 5 J. Palliative Med. 729, 732 (2002).
Relying on LARs
In event of incapacity, subject’s LAR would make
decision about research participation
Predictions by surrogate decision-makers re: end
of life care decisions made with 68% accuracy
(U.S. Dep’t of Health & Human Services, Advance Directives and Advance Care Planning: Report
to Congress, Aug. 2008, http://aspe.hhs.gov/daltcp/reports/2008/ADCongRpt.pdf)
– Surrogate may guess incorrectly about desire of
individual to participate or not
Advance directive will help ensure participant’s
wishes will be carried out
Advance Directives
“Advance Directive” is umbrella
Several types of advance directives that can be
– Living will
– Health Care Surrogate/Proxy, Durable Power of
Executing advance directives that specifically
address research participation (esp. with re: to
specific study/studies), who LAR is, can help
ensure wishes re: research participation are
A Few Words of Caution
Some criticize ADs, saying they aren’t
followed, aren’t produced in time
Some surrogates/proxies may disagree
with participant’s stated wishes
– Ugly situation!!!
If not study-specific, an AD pertaining to
research could be harder to follow
Ethics of Research Still
This is not an argument for allowing any
research to go forward as long as subjects
Autonomy is not letting subjects make
whatever decision they want about
whatever may be offered
IRB review and judgment, ethical research
is still important!
Terminally ill persons perceived as vulnerable
research subjects for variety of reasons
Some of these reasons more persuasive than
But law empowers terminally ill to make lots of
decisions autonomously outside of research
That empowerment should translate to research
setting because of required informed consent
process, possibility of executing advance directive
addressing research participation
Thank You!
Lauren Solberg, JD, MTS
UF College of Medicine
[email protected]

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