MedicReS Winter School 2017 Vienna - Ethics of Cancer Trials - Adil E. Shamoo

MedicReS Good Biostatistical & Publication
Practice in Cancer Research with "Real World
Data"
February 13 - 14, 2017 VIENNA
A Comprehensive Introduction to the Ethical
Issues at stake in the conduct of Cancer
Research
Adil E. Shamoo, Ph.D.
University of Maryland School of Medicine
and
Consultant
108 N. Greene Street
Baltimore, MD 21201
Tel #: 410-706-3327
Mobile: 301-538-2599
E-mail: ashamoo@som.umaryland.edu
Adil E. Shamoo, Ph.D.

The Talk will Cover:
1. Brief history of use of human subjects in Research
2. Purpose of research with human subjects
3. The purpose of Clinical trials
a. Phases of clinical trials
b. Purpose of Phase I trials
4. Unique ethical issues in use of Cancer patients in
clinical trials
a. Phase I trials
b. Use of Placebo
5. Conclusions on how to proceed ethically with
clinical trials with Cancer patients.

Walter Reed
YELLOW FEVER EXPERIMENTS
1900

Walter Reed with two co-investigators. One investigator died. 33 subjects
(18 Americans + 15 Spanish immigrants). 6 subjects died.
It is understood that at the completion of these
experiments, within two months from this date, the
undersigned will receive the sum of $100 in
American gold and that in case of his contracting
yellow fever at any time during his residence in this
camp, he will receive in addition to that sum a
further sum of $100 in American gold, upon his
recovery and that in case of his death because of
this disease, …to[the disignee]

NUREMBERG CODE
1947
Nuremberg Military Tribunal Control Council
Law No. 10, 1947

Historical OverviewHistorical Overview
 Nuremburg Code – 1949Nuremburg Code – 1949
 National Research Act –National Research Act –
Created the National Commission for the Protection of HumanCreated the National Commission for the Protection of Human
Subjects of Biomedical and Behavioral Research (July 12,Subjects of Biomedical and Behavioral Research (July 12,
1974)1974)
Belmont Report –Belmont Report –
Ethical Principles and Guidelines for the Protection ofEthical Principles and Guidelines for the Protection of
Human Subjects of Research. Report of the NationalHuman Subjects of Research. Report of the National
Commission for the Protection of Human Subjects ofCommission for the Protection of Human Subjects of
Biomedical and Behavioral Research, 1979Biomedical and Behavioral Research, 1979
 Declarations of Helsinki, 1964 - 2014Declarations of Helsinki, 1964 - 2014

Nuremburg Code
• Voluntary consent
• Yield fruitful results otherwise unobtainable
• Based on animal experiments
• Avoid physical and mental suffering
• Not done if injury expected
• Risk less than importance of problem
• Protect subject from injury
• Conducted by qualified people
• Termination by subject
• Termination by investigator
• Voluntary consent
• Yield fruitful results otherwise unobtainable
• Based on animal experiments
• Avoid physical and mental suffering
• Not done if injury expected
• Risk less than importance of problem
• Protect subject from injury
• Conducted by qualified people
• Termination by subject
• Termination by investigator

Nuremburg Code Principle # 1
The voluntary consent of the human subject isThe voluntary consent of the human subject is
absolutely essential.absolutely essential. This means that the personThis means that the person
involved should have legal capacity to give consent;involved should have legal capacity to give consent;
should be so situated as to be able toshould be so situated as to be able to exercise freeexercise free
power of choice without the intervention of anypower of choice without the intervention of any
element of force, fraud, deceit, duresselement of force, fraud, deceit, duress, over-reaching, over-reaching
or other ulterior form of constraint or coercion; andor other ulterior form of constraint or coercion; and
should have sufficient knowledge and comprehensionshould have sufficient knowledge and comprehension
of the elements of the subject matter involved as toof the elements of the subject matter involved as to
enable him to make an understanding andenable him to make an understanding and
enlightened decision.enlightened decision.

Belmont ReportBelmont Report
(National Commission, April 18, 1979)(National Commission, April 18, 1979)
Informed Consent:Informed Consent:
1. Sufficient1. Sufficient
Information.Information.
2. Comprehension.2. Comprehension.
3. Free of Duress and3. Free of Duress and
Coersion.

The Belmont ReportThe Belmont Report
(National Commission, April 18, 1979)(National Commission, April 18, 1979)
 Respect for Persons (Autonomy)Respect for Persons (Autonomy)
– Individual autonomyIndividual autonomy
– Protection of individuals with reduced autonomyProtection of individuals with reduced autonomy
 Beneficence (Risk/Benefit)Beneficence (Risk/Benefit)
– Maximize benefits and minimize harmsMaximize benefits and minimize harms
 JusticeJustice
– Equitable distribution of research costsEquitable distribution of research costs
and benefitsand benefits

(OHRP)(OHRP)45 CFR 4645 CFR 46 (FDA)(FDA) 21 CFR 50,5621 CFR 50,56
THE BELMONT REPORTTHE BELMONT REPORT
45 CFR 46, 45 CFR 8386 (Jan 26, 1981)
21 CFR 56, 46FR 8942 (Jan. 27, 1981)
Codified as US Regulations

4. Unique ethical issues in use of Cancer patients in clinical trials
a. Phase I trials
b. Use of Placebo
5. Conclusions on how to proceed ethically with clinical trials
with Cancer patients.

 "Medical Treatment" means the"Medical Treatment" means the
management and care of a patient tomanagement and care of a patient to
combat disease or disorder.combat disease or disorder.
(https://www.google.com/webhp?sourceid=chrome-instant&ion=1&espv=2&ie=UTF-(https://www.google.com/webhp?sourceid=chrome-instant&ion=1&espv=2&ie=UTF-
8#q=medical+treatment+definition+osha)8#q=medical+treatment+definition+osha)
 A clinical trial is one type of clinicalA clinical trial is one type of clinical
research that follows aresearch that follows a pre-defined planpre-defined plan oror
protocol. … [P]articipants …can accessprotocol. … [P]articipants …can access
experimental treatmentsexperimental treatments and help othersand help others
by contributing to medical research.by contributing to medical research.
(https://www.nichd.nih.gov/health/clinicalresearch/Pages/index.aspx(https://www.nichd.nih.gov/health/clinicalresearch/Pages/index.aspx
))

Solely for the Benefit of theSolely for the Benefit of the
patientpatient
VsVs
Public GoodPublic Good
(With few exceptions)(With few exceptions)

The Need for Clinical TrialsThe Need for Clinical Trials
 To reduce pain and SufferingTo reduce pain and Suffering
 Seeking new and/or improved treatmentSeeking new and/or improved treatment
(drug, device, biologic, surgical,... Etc)(drug, device, biologic, surgical,... Etc)
 Safer treatment (Less side effects)Safer treatment (Less side effects)
 Less expensive treatmentLess expensive treatment

RisksRisks
 Reasonably foreseeable risks,Reasonably foreseeable risks,
discomforts, inconveniences anddiscomforts, inconveniences and
hardships must be described in full.hardships must be described in full.
– Psychological/Emotional Risks As WellPsychological/Emotional Risks As Well
As PhysicalAs Physical
– Risk of Breech/Loss of ConfidentialityRisk of Breech/Loss of Confidentiality
 If additional risks become known,If additional risks become known,
participant will be contacted at onceparticipant will be contacted at once

Benefits of the StudyBenefits of the Study
 What benefits, if any, shouldWhat benefits, if any, should
participants reasonably expect toparticipants reasonably expect to
receive?receive?
 Be frank. Do not overestimate. ThereBe frank. Do not overestimate. There
may be no benefit other than that ofmay be no benefit other than that of
helping society.helping society.
 Payment to subjectPayment to subject is notis not considered aconsidered a
benefitbenefit

Phases of Clinical TrialsPhases of Clinical Trials
 Phase 0Phase 0 (Rarely used, FDA approval, Very few subjects, No(Rarely used, FDA approval, Very few subjects, No
benefits)benefits)
 Phase IPhase I Safety, minimal toxic dose (MTD), (Healthy subjectsSafety, minimal toxic dose (MTD), (Healthy subjects
(20-100)(20-100), exception Cancer patients, usually in-patient), exception Cancer patients, usually in-patient)
 Phase IIPhase II (Efficacy and side effects, Subjects with the(Efficacy and side effects, Subjects with the
disorderdisorder 25-30025-300, In Cancer patients: No placebo control (no, In Cancer patients: No placebo control (no
treatment or sham) but standard therapy, in-patients,treatment or sham) but standard therapy, in-patients,
randomized,randomized,
 Phase IIIPhase III (Safety and efficacy, better treatment compared(Safety and efficacy, better treatment compared
to standard drug, subjects with disorder,to standard drug, subjects with disorder, 300-3000300-3000 subjects)subjects)
 Phase IV, (Phase IV, (Safety and efficacySafety and efficacy few tens of thousandsfew tens of thousands))

Phase I clinical trials inPhase I clinical trials in
general are:general are:
““ethical and necessary”ethical and necessary” (Lipsett, 1982,(Lipsett, 1982,
JAMA: 248(8), p. 942)JAMA: 248(8), p. 942)

Phase I Trials # 1Phase I Trials # 1
Group of SubjectsGroup of Subjects
1.1. Healthy VolunteersHealthy Volunteers
2.2. Far-advanced cancer patientsFar-advanced cancer patients
3.3. Others (e.g. Vaccine in children)Others (e.g. Vaccine in children)

Phase I Trials # 2Phase I Trials # 2
PurposePurpose (To attain(To attain “generalizable knowledge”“generalizable knowledge”
(45 CFR46)(45 CFR46)
1.1. ToxicityToxicity
2.2. Minimum Toxic Dose (MTD)Minimum Toxic Dose (MTD)

Safety of Phase ISafety of Phase I
Clinical Trials #1Clinical Trials #1
Healthy SubjectsHealthy Subjects
 No specific data. Aggregate data onlyNo specific data. Aggregate data only
 Data on childrenData on children’s safety in vaccine’s safety in vaccine
trialstrials

Tragedies in First UseTragedies in First Use
 1996- Hoiyan Wan,1996- Hoiyan Wan, 19 years old healthy volunteet (med.st.),19 years old healthy volunteet (med.st.),
Univ. of Rochester. Lidocaine during bronchoscopy.Univ. of Rochester. Lidocaine during bronchoscopy.
 1999- Jesse Gelsinger,1999- Jesse Gelsinger, 18 years old, gene therapy18 years old, gene therapy
 2001- Ellen Roche,2001- Ellen Roche, 24 years old healthy volunteer,24 years old healthy volunteer,
Hexamethonium.Hexamethonium.

Safety of Phase ISafety of Phase I
Clinical Trials #2Clinical Trials #2
Far-advanced cancer patientsFar-advanced cancer patients
(Decoster et al.,(Decoster et al., 19901990; Estey et al., 1986); Estey et al., 1986)
 Overall Response Rate: 5%Overall Response Rate: 5% (variation 0(variation 0
to 40%)to 40%)
 Overall Mortality Rate: 0.5%Overall Mortality Rate: 0.5%
(European Journal of Cancer, Arkrnau et. al. July(European Journal of Cancer, Arkrnau et. al. July 20082008, Volume 44,, Volume 44,
Issue 11, Pages 1536–1540.)Issue 11, Pages 1536–1540.)
 80% survival (for total of 97 patients)80% survival (for total of 97 patients)

Reasons to Enrolling inReasons to Enrolling in
Cancer Trials?Cancer Trials?
 85%85% Because of possibleBecause of possible
therapeutic benefitstherapeutic benefits
 11%11% Advice of physicianAdvice of physician
 4%4% Family pressuresFamily pressures
(Daugherty et al., 1995, 13(5):1062-1072)(Daugherty et al., 1995, 13(5):1062-1072)

Best things about Phase IBest things about Phase I (Healthy(Healthy
subjects open ended; multiple responses)subjects open ended; multiple responses)
(Kass et al,(Kass et al, CLINICAL PHARMACOLOGY & THERAPEUTICS |CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 82 NUMBER 2 |VOLUME 82 NUMBER 2 |
AUGUST 2007)AUGUST 2007)
 People I’ve metPeople I’ve met
56.7%56.7%
 The moneyThe money
55.0%55.0%
 Contributing to scienceContributing to science
45.0%45.0%
 Could relaxCould relax
30.0%30.0%
 Personal health/benefitsPersonal health/benefits
20.0%20.0%

http://www.statnews.com/2016/11/23/cancer-patients-fda-juno/

https://www.nytimes.com/2017/01/28/opinion/sunday/a-crime-in-the-cancer-lab.html?ref=opinion

Retraction WatchRetraction Watch

Understanding InformedUnderstanding Informed
Consent in Cancer TrialsConsent in Cancer Trials
 93 %93 % Claimed understood all of theClaimed understood all of the
information.information.
 60%60% Claimed understood, most ofClaimed understood, most of
the information.the information.
 33%33% Able to state the purpose ofAble to state the purpose of
the trials.the trials.
(Daugherty et al., 1995, 13(5):1062-1072(Daugherty et al., 1995, 13(5):1062-1072))

Cancer TrialsCancer Trials
(Quality of Informed Consent(Quality of Informed Consent
Forms)Forms)
 99%99% Mentioned the trials as researchMentioned the trials as research
 92%92% Said the trial is testing for safetySaid the trial is testing for safety
 67%67% Mentioned death as riskMentioned death as risk
 10%10% Mentioned cure as possibleMentioned cure as possible
benefitbenefit
 100%100% Use the termUse the term “treatment”“treatment”
(Horng et al (2002), N. Engl. J. Med. 347(26):2134-2140)(Horng et al (2002), N. Engl. J. Med. 347(26):2134-2140)

Phase I TrialsPhase I Trials
(Risk/Benefits Ratio)(Risk/Benefits Ratio)
Comparison Between Far-Advanced CancerComparison Between Far-Advanced Cancer
Patients and Healthy Subjects# 1Patients and Healthy Subjects# 1
Adult HealthyAdult Healthy SubjectSubject
Cancer PatientCancer Patient
a.a. Health needsHealth needs NoNo YesYes
b.b. Scientific validityScientific validity YesYes YesYes
c.c. Medical BenefitMedical Benefit
Direct Medical BenefitDirect Medical Benefit NoNo May beMay be
Potential Medical BenefitPotential Medical Benefit NoNo YesYes
Public GoodPublic Good YesYes YesYes
Compensation for injuryCompensation for injury ?? ??
n RiskRisk low?low? low?low?

Phase I Clinical Trials, Justice and PaymentPhase I Clinical Trials, Justice and Payment
to Subjects Comparison Between Far-to Subjects Comparison Between Far-
Advanced Cancer Patients and HealthyAdvanced Cancer Patients and Healthy
Subjects # 2Subjects # 2
Adult HealthyAdult Healthy Far-Far-
AdvancedAdvanced
SubjectSubject CancerCancer
PatientPatient
JusticeJustice May beMay be YesYes
Payment to SubjectPayment to Subject Very importantVery important Not importantNot important
Expense modelExpense model Not importantNot important appropriateappropriate
Labor modelLabor model AppropriateAppropriate InappropriateInappropriate
Market modelMarket model May be appropriateMay be appropriate InappropriateInappropriate

Motivations to Enroll inMotivations to Enroll in
Phase I Clinical TrialsPhase I Clinical Trials
Healthy SubjectsHealthy Subjects
1.1. MoneyMoney
2.2. AltruismAltruism
3.3. Health careHealth care
Far-advanced Cancer PatientsFar-advanced Cancer Patients
1.1. Health needsHealth needs
2.2. Potential direct medical benefitsPotential direct medical benefits
3.3. HopeHope
4.4. Potential better carePotential better care
5.5. AltruismAltruism

4. Unique ethical issues in use of Cancer patients in clinical
trials
a. Phase I trials
b. Use of Placebo
5. Conclusions on how to proceed ethically with clinical trials
with Cancer patients.

Unique Ethical and SafetyUnique Ethical and Safety
Issues forIssues for Healthy SubjectsHealthy Subjects
in Phase I Clinical Trialsin Phase I Clinical Trials
1.1. No medical benefits.No medical benefits.
2.2. Risks are small but real.Risks are small but real.
3.3. This is, most likely, the first use of this drug orThis is, most likely, the first use of this drug or
chemical in human beings.chemical in human beings.
4.4. The purpose of the trial is to test for toxicityThe purpose of the trial is to test for toxicity
and maximally tolerated dose.and maximally tolerated dose.
5.5. The degree of expected adverse eventsThe degree of expected adverse events
6.6. Amount of payment and why?Amount of payment and why?

Unique Ethical ConcernsUnique Ethical Concerns
for Cancer patients infor Cancer patients in
Clinical TrialsClinical Trials
1.1. Phase I TrialsPhase I Trials
2.2. Use of Placebo in TrialsUse of Placebo in Trials

Unique Ethical and SafetyUnique Ethical and Safety
Issues forIssues for Cancer SubjectsCancer Subjects inin
Phase I Clinical TrialsPhase I Clinical Trials
1.1. Usually no medical benefits.Usually no medical benefits.
2.2. ItIt maymay have some benefits (no guarantees) inhave some benefits (no guarantees) in
reducing the progress of Cancerreducing the progress of Cancer
3.3. Risks could be large.Risks could be large.
4.4. This is, most likely, the first use of this drug orThis is, most likely, the first use of this drug or
chemical in human beings.chemical in human beings.
5.5. The purpose of the trial is to test for toxicity andThe purpose of the trial is to test for toxicity and
maximally tolerated dose.maximally tolerated dose.
6.6. The degree of expected adverse eventsThe degree of expected adverse events
7.7. Amount of payment and why?Amount of payment and why?

Are there therapeutic benefits
from Cancer Phase I Trials?
• Controversial
• Differ depending on roles in
trials
• Is it a treatment?

Clinical Treatment Vs Clinical
Research Equipoise
• “The Ethics of research and of therapy are
fundamentally different, and clinical equipoise
should be abandoned” (Miller and Brody,
2003)
• Freedman (1987, Original author of Research
equipoise) said in ref to Phase I trial: “[T]he
reason for conducting the [Phase I] trial is to
discover the point at which a compound is too
poisonous to administer.”

Evidence-Based Medicine (EBM)
(Shamoo, 2008)
• Treatment: EBM is the basis of treatment
agent.
• Research: An Experiment to find what agent
provides therapy - treatment.
• Never there is an equipoise between
treatment and research especially in Phase I
trials.

Cancer Clinical Trials Investigators
and few ethicists Offer:
• RCT design issues and informed consent
(Hamilton and Peppercorn, 2011)
• Quality of Informed consent (Tatterall, 2001)
• Use of ethics of social justice and patient
advocacy (Burke, 2014)
• ASCO (2016) uses terms as “treatment” and
“Therapeutic benefits” in Phase I trials.

American Society of Clinical Oncology Policy Statement
Update: The Critical Role of Phase I Trials in Cancer Research
and Treatment, 2015 http://ascopubs.org/doi/pdf/10.1200/JCO.2014.58.2635
“Direct Medical Benefit
Many participants in phase I trials in cancer
have the “prospect of a direct medical
benefit.”37p617
“There are instances in phase I trials in cancer
where the agents being tested have had a
significant therapeutic impact on large
numbers of patients.”

American Society of Clinical Oncology Policy Statement
, 2016 Update: (http://ascopubs.org/doi/pdf/10.1200/JCO.2016.70.4692)
Jeffery Weber, MD.,Ph.D. Et al.
• “phase I trials have therapeutic intent and that such
intent is necessary, but not sufficient, to support
conduct of such trials in patients with cancer. As
noted in ASCO’s 2015 policy statement update on
this topic,2 these trials must also have the potential
to provide clinical benefit. In offering an
interventional trial, the physician and patient have
the goal of attempting to treat the cancer. The
same goal applies when a physician and patient
pursue therapeutic options outside a clinical trial”

The truth about phase I clinical trialsThe truth about phase I clinical trials
in Cancer patientsin Cancer patientshttphttp
://www.cancer.net/navigating-cancer-care/how-cancer-treated/clinical-trials/phase-i-clinical-trials-cancer-treatment://www.cancer.net/navigating-cancer-care/how-cancer-treated/clinical-trials/phase-i-clinical-trials-cancer-treatment))
Jeffrey S. Weber, MD, PhDJeffrey S. Weber, MD, PhD
 Many people think that clinical trials, especially phase I trials, aren’t anMany people think that clinical trials, especially phase I trials, aren’t an
option until they try all other options.option until they try all other options. In fact, clinical trials are always aIn fact, clinical trials are always a
treatment optiontreatment option. Sometimes a clinical trial is as good as or better than. Sometimes a clinical trial is as good as or better than
standard therapy for some cancers. Often people have more choices to bestandard therapy for some cancers. Often people have more choices to be
in a clinical trial the earlier they are in the treatment process.in a clinical trial the earlier they are in the treatment process.
 Some patients would rather get standard treatments because they thinkSome patients would rather get standard treatments because they think
phase I trials won’t work. However, research and drug discovery is movingphase I trials won’t work. However, research and drug discovery is moving
fast. That means the standard treatment may not always be the bestfast. That means the standard treatment may not always be the best
option.option.
 As doctors learn more about which drugs treat which cancers best, manyAs doctors learn more about which drugs treat which cancers best, many
patients experience a: Stabilization of the cancer, which means there’s nopatients experience a: Stabilization of the cancer, which means there’s no
new growth; or Response from the drug being tested, usually measured asnew growth; or Response from the drug being tested, usually measured as
a tumor shrinking or going away.a tumor shrinking or going away.

Arguments in favor or against access toArguments in favor or against access to
Phase I agents # 1Phase I agents # 1
(Schuklenk and Lowry, British Medical Bulletin 2009; 89: 7-22)(Schuklenk and Lowry, British Medical Bulletin 2009; 89: 7-22)
 In Favor:In Favor: Based on Autonomy living in a freeBased on Autonomy living in a free
society of John Stewart Mill.society of John Stewart Mill.
““An autonomous choice is a choiceAn autonomous choice is a choice
undertaken by a competent person who isundertaken by a competent person who is
expressing her reflective decision that isexpressing her reflective decision that is
based on the information available and thatbased on the information available and that
is consistent with the values that areis consistent with the values that are
authentically her own at the time when sheauthentically her own at the time when she
makes a particular decision.”makes a particular decision.”

Arguments in favor or against ofArguments in favor or against of
access to Phase I agents # 2access to Phase I agents # 2
(Schuklenk and Lowry, British Medical Bulletin 2009; 89: 7-22)(Schuklenk and Lowry, British Medical Bulletin 2009; 89: 7-22)
 Against.Against.
““[S]uch access is not in the interest of[S]uch access is not in the interest of
the individual patients who seek it, isthe individual patients who seek it, is
not in the collective interest of currentnot in the collective interest of current
and future sufferers of a disease takenand future sufferers of a disease taken
as a group and is not in the publicas a group and is not in the public
interest generally.”interest generally.”

•Use of Placebo in Clinical
Trials

Ethics of Placebo in Cancer Clinical Trials
(in RCT) # 1 (Daugherty et. al., 2008)
• For over fifty years, Placebo was not used in
Cancer Trials
• Many groups and stakeholders object to use
of Placebo.
• Only 15% Cancer patients willing to take
Placebo.
• Cancer Trials are OK in case of: No effective
standard treatment; ST has low
effectiveness; High toxicity.

• All ethical and regulatory compliance must be
fulfilled or justified.
• It can be justified for:
– new metastatic cancer
– No approved, effective therapy exist, current treatment
is minimally effective; life-threatening adverse events
Objections are: No tumor response, No improved quality of
life; No prolongation of life.
All ethical and regulatory compliance must be fulfilled or
justified.
Ethics of Placebo in Cancer Trials (in RCT)
# 2 (Daugherty et. al., 2008)

In conclusion, for far-advanced
Cancer patients
• Research (Phase I and Placebo) can be ethically
justified if:
– no treatment alternative,
– appeal to altruism to help others,
– reduce risks,
– Use DSMB, and
– (mostly) in-patient.
– Be honest and forthright in the informed consent. Use
terms: experimental treatment, it may help you, help
others, …

MedicReS Winter School 2017 Vienna - Ethics of Cancer Trials - Adil E. Shamoo

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