Empowerment of Terminally Ill Research Subjects

Lauren Solberg, JD, MTSAssistant Professor,

Program in Bioethics, Law & Medical ProfessionalismDepartment of Community Health & Family Medicine;

Departments of Aging and Geriatric Research & Psychiatry

Uniformed Services University of the Health SciencesFebruary 10, 2014

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 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 Ill as Vulnerable Research Population

Google “terminally ill research population” (without quotes)

What results do you see?

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…

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

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 limited

http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

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

http://www.hhs.gov/ohrp/archive/irb/irb_chapter6ii.htm#g8

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

“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

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 SurvivalTerminally 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”

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

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 http://www.fda.gov/regulatoryinformation/guidances/ucm126429.htm

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 = 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

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-ArgumentSubject 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”

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 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

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)

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 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 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 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 Law26 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)

http://www.guttmacher.org/statecenter/spibs/spib_OMCL.pdf

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.

Vermont

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

Montana

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

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.”

https://newmexico.tylerhost.net/ServeDocument.ashx?SID=0730da82-c2ce-4331-9d34-98fe74190124&RID=001664dd-e045-4d6c-b5ce-1294189b0a7a

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, 1997Dignified 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 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

Because…

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

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 ElementsStatement 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

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

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 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

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!

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!

ConclusionsTerminally 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!

Lauren Solberg, JD, MTS

UF College of Medicine

lbsolberg@ufl.edu

352-273-5142