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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;

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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
Goals of This Session
  • Discuss perceptions of terminally ill persons as vulnerable research subjects, present counterarguments
  • Identify ways terminally ill individuals are empowered under law to make clinical care decisions
  • Describe how informed consent process, other mechanisms can empower terminally ill individuals in research context, combat/counteract perceptions of vulnerability
what is terminally i ll
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 condition

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 i ll as vulnerable research population
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
Vulnerability Perceived Regardless of Research Type?
  • Yes
  • 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
Perception of Vulnerability of Terminally Ill Based On…
  • Interpretation of federal regulations, other documents
  • 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 regulations
Vulnerability Under the Regulations
  • 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
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 d1
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
The Belmont Report
  • Published 1979
  • Terminally ill listed among populations that may be “incompetent”
  • Concern that comprehension may be limited

ohrp s irb guidebook
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
Vulnerable Under the Regs?
  • Terminally ill populations not specifically mentioned in federal human subjects research regulations as vulnerable populations
    • 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
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 vulnerability
Misunderstanding of Research = Vulnerability
  • 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
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 misconception)

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
“Therapeutic Doublethink”
  • Doublethink – from Orwell’s 1984 - having 2 contradictory beliefs, accepting both of them
  • 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
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
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
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 vulnerability
Cognitive Impairment = Vulnerability
  • 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 decisions
Inability to Make Voluntary Decisions

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?
counter argument
  • Subject doesn’t need to know if intervention will work
  • 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”

UdoSchüklenk & 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
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 I-eligible 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
Limited Access to Unapproved Drugs
  • Clinical trials likely only way someone with terminal illness will access investigational drug
    • 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
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
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 therapy
  • Clinical testing ok under FDCA, unfettered access is not

U.S. v. Rutherford, 442 U.S. 544 (1979)

abigail alliance v von eschenbach
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
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
Empowerment Under the Law
  • Statutes and Regulations
  • Court opinions
right to withhold withdraw treatment
Right to Withhold/Withdraw Treatment

“It cannot be disputed that the Due Process Clause protects an interest in life as well as an interest in refusing life-sustaining medical treatment.”

Cruzan v. MO Dep’t of Health, 497 U.S. 261 (1990)

*Competent people have Due Process right to refuse life-sustaining treatment

minors rights under the law
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 consent)

oregon washington
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 purpose
  • 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 voters

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 policy
    • Consent exception under MT law could apply to physicians assisting in suicide (no homicide prosecution)
new mexico
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
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
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
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
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 make clinical decisions
Empowerment to Make Clinical Decisions…
  • 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
Informed Consent Empowers Research Subjects


  • By regulation, informed consent process is detailed
    • 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
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
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
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
good verbal discussion can help compensate
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
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
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 populations

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
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,
    • 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 Directives
  • “Advance Directive” is umbrella
  • Several types of advance directives that can be executed
    • Living will
    • Health Care Surrogate/Proxy, Durable Power of Attorney
  • 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 honored
a few words of caution
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 important
Ethics of Research Still Important!
  • This is not an argument for allowing any research to go forward as long as subjects consent
  • 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 others
  • But law empowers terminally ill to make lots of decisions autonomously outside of research context
  • That empowerment should translate to research setting because of required informed consent process, possibility of executing advance directive addressing research participation
thank you
Thank You!

Lauren Solberg, JD, MTS

UF College of Medicine