Principles of

Clinical Pharmacology
 Ethics in Adult
Clinical Pharmacology

Dr. Ezekiel J. Emanuel, MD, PhD

Diane v. S. Levy & Robert M. Levy Professor
Vice Provost for Global Initiatives
Chair, Department of Medical Ethics & Health Policy
University of Pennsylvania
NIH Bioethics Module: Research Ethics
Ezekiel J. Emanuel, M.D., Ph.D.
University of Pennsylvania
 History of Research Ethics
• 1767: William Watson, physician at the Foundling
Hospital in London sought to test 2 claims related
to small pox inoculation:
1. Was preparing patients with purgatives beneficial?
2. What was the best source of the inoculum – early or
late lesions?
 History of Research Ethics
• First Trial
• 10 mercury and jalap (a strong laxative)
• 10 senna and syrup of roses (a mild laxative)
• 11 no medications

• All had the same diet, similar clothes, played in the

same fields and slept in the same dormitories.
• Pus from early pock.
• Endpoint was number of pocks on each child.
 History of Research Ethics
• Watson’s experiments had:
• Deliberate study design
• Controls—matched subjects

• Controlled circumstances

• Quantitative endpoint

“Clinical science began in 1767”

 History of Research Ethics
• 1938: First placebo control in a trial of cold vaccines.
• 1948: First modern randomized placebo controlled
trial of Streptomycin for TB.
 History of Research Ethics
• The first recorded mention of consent occurs in a
1767 British law suit
(Slater v. Baker & Stapleton)

• Two physicians were held liable for re-breaking a

bone because:
• “It appears from the evidence of the surgeons that it
was improper to disunite the callous without consent;
this is the usage and law of surgeons…”
 History of Research Ethics
• 1897: Sanarelli announced he discovered the
bacillus of yellow fever and produced yellow fever
in 5 patients.

• 1898: Osler condemns Sanarelli:

“To deliberately inject a poison of known high

degree of virulency into a human being, unless you
obtain that man’s sanction, is not ridiculous, it is
criminal.”
Walter Reed
 History of Research Ethics
• 1900: Yellow Fever Board established in USA
• 1901: Walter Reed decides that ethics of research
required:
• Self-experimentation
• Written agreements with other subjects
• Payment in gold
• Restriction to adult subjects
• Using the phrase “with his full consent” in all journal articles.
8 Ethical Requirements
1. Collaborative partnership
2. Social value
3. Scientific validity
4. Fair subject selection
5. Favorable risk-benefit ratio
6. Independent review
7. Informed consent
8. Respect for human subjects
1 Collaborative Partnership

• To be ethical, clinical research must involve the

community in which it occurs.

• This requires:
• Community participation in planning, conducting and
overseeing research, and integrating research results into
the health system.
• Avoidance of supplanting existing health care services and
the sharing rewards with the community.
1 Collaborative Partnership

• Mechanisms to achieve collaborative partnership

may include the input of:

• Community advisory boards

• Patient advocates on scientific advisory boards

• Advocates for funding of research

2 Social Value

• To be ethical, clinical research must lead to

improvements in health or advancement in
generalizable knowledge.

• Must consider how the research will improve health

of:
• The participants in the research
• The community in which research is conducted
• The world
2 Social Value

• Valueless research includes:

• Non-generalizable studies
• “Me too” studies
• Non-disseminated research
3 Scientific Validity

• Research must be conducted in a methodologically

rigorous manner that is practically feasible.

• To be ethical the research must produce reliable

and valid data that can be interpreted.
3 Scientific Validity

• Invalid research includes underpowered studies,

studies with biased endpoints, instruments, or
statistical tests, and studies that cannot enroll
sufficient subjects.
4 Fair Subject Selection

• The scientific objectives of the study—not

vulnerability or privilege—should guide inclusion
criteria and targeted populations.

• Lowering risk and enhancing generalizability can

then be considered.
4 Fair Subject Selection

• Convenient groups should not be selected.

• Groups cannot be excluded without scientific
reasons.
• Higher risk is a reason to exclude certain groups.
• Should not select rich, politically powerful or
otherwise well connected people for “promising
research” studies.
5 Favorable Risk-Benefit Ratio

4 Step Evaluation
1) Risks identified, assessed and minimized
• Risks include:
• Physical —death, disability, infection
• Psychological —depression and anxiety
• Social —discrimination
• Economic —job loss
• Evaluate magnitude & likelihood of harm
• Identify mechanisms to minimize risk
5
Favorable Risk-Benefit Ratio
4 Step Evaluation
2) Potential benefits to individual participants enhanced
• Consider physical, psychological, social, and economic
benefits to the individual
• Consider only benefits from research interventions not
benefit from added health services or payment that are not
necessary to the research goals
5
Favorable Risk-Benefit Ratio
4 Step Evaluation

3) If potential benefits to the individual outweigh risks to

the individual then proceed

4) If risks outweigh benefits to the individual, then evaluate

risks against social benefit of knowledge gained.
6 Independent Review

• Because investigators have multiple legitimate interests,

they have potential conflicts of interest. Independent review
of the research minimizes these conflicts.
• Independent review also assures society it will not benefit
from abuse of subjects.
7 Informed Consent

• Informed consent ensures individuals decide

whether they enroll in research and whether
research fits with their own values, interests, and
goals.

• For those who cannot consent—such as children

and mentally impaired—must ensure that research
fits with their interests.
7 Informed Consent

What constitutes informed consent?

7 Informed Consent

Informed consent consists of 4 elements

1. Competence of the subject

2. Disclosure of information to the subject

3. Understanding or comprehension by the subject

4. Voluntariness of the decision

7 Informed Consent

Federal regulations require 8 elements to be included in

every informed consent form.
1. Purpose and duration of 5. Confidentiality of records
participation 6. Compensation for injuries
2. Risks 7. Person to contact for
3. Alternatives answers to questions
4. Benefits 8. Voluntariness and right to
withdraw
8 Respect for Human Subjects

The ethical requirements of research do not end with a

signed consent document. They also include:
1) Monitoring subjects’ welfare
2) Protecting confidentiality
3) Permitting withdrawal
4) Providing new information
5) Informing subjects of what was learned from the
research
 8 Ethical Requirements

• All 8 requirements are necessary and essential to

make clinical research ethical.

• Independent review and informed consent are

procedural requirements to ensure certain values are
achieved. Other procedures may achieve these
values. In some circumstances, independent review
and informed consent can be waived.
 8 Ethical Requirements

In fulfilling the 8 ethical requirements, conflicts can

occur.

• What is fair in subject selection may increase risks.

• What enhances scientific validity may increase risks.

• What is necessary to respect enrolled subjects or

obtain informed consent may compromise scientific
validity.
 8 Ethical Requirements

• No simple formula for resolving conflicts.

• Adjust design to meet the requirements. This is

sometimes termed “balancing” or “weighing” or
“specifying” the principles.

• The important point is to be clear about what is

being done and give reasons why.
 8 Ethical Requirements

Two different approaches

may both be ethical.
 8 Ethical Requirements

• All 8 ethical requirements are universal. They do not

apply only to the US or Europe. They apply to clinical
research everywhere.

• The 8 ethical requirements must be adapted to the local

health, economic, cultural and technological
circumstances. For instance, disease risk may affect
risk-benefit evaluation.
8 Ethical Requirements
1. Collaborative partnership
2. Social value
3. Scientific validity
4. Fair subject selection
5. Favorable risk-benefit ratio
6. Independent review
7. Informed consent
8. Respect for human subjects
Ethics of Phase I Oncology
 Example: Geraldine

• 55 yo female
• Had a R breast mass
• Excision—0.9x0.5 cm mass, 0/15 lymph nodes with
ER=0 and PR=538.
• Work-up negative.
• Received XRT and no chemotherapy.
• 3 years later Recurrence in liver and lungs.
 Geraldine
• Treated with chemotherapy.
• When cancer progressed in her liver we discussed
hospice and Phase I trials.
• She wanted to “fight my cancer”.
• First Phase I agent failed after 2 cycles.
• She wanted another Phase I agent rather than
hospice.
• After the second agent failed, she had substantial
pedal edmea, could barely walk, but came to clinic
wanting yet another Phase I agent.
8 Ethical Requirements
1. Collaborative partnership
2. Social value
3. Scientific validity
4. Fair subject selection
5. Favorable risk-benefit ratio
6. Independent review
7. Informed consent
8. Respect for human subjects
 Criticisms of Phase I Oncology Research

• The criticisms of Phase I oncology research focus on two of the 8

principles:

• Risk-benefit ratio is unfavorable.

• Informed Consent: Terminally ill patients cannot provide valid

informed consent.
 Unfavorable Risk-Benefit Ratio

• Phase I research is not intended to benefit the

individual participants.

• Phase I research has some risks to the individual

participants.

• With no benefits but with risks, the risk/benefit

assessment is inherently unfavorable.
 Unfavorable Risk-Benefit Ratio

• If the risk/benefit assessment is unfavorable for

individual participants, then the research is conducted
only to gain knowledge for society.

• If the primary beneficiary of research is society, then

individual patients are exploited for the benefit of
society.
 Unfavorable Risk-Benefit Ratio

The fact that there is no treatment for the condition

does not make any intervention “therapeutic” or
even “probably therapeutic.” Phase I cancer drug
research may not be performed on terminally ill
subjects under these guidelines because there is no
reasonable probability that it will benefit the
subjects.

George Annas
 Avoiding Exploitation by Informed Consent

Relying on valid informed consent by the research

participants has been the response to the possibility of
exploitation of patients in Phase I oncology research.
 Unfavorable Risk-Benefit Ratio
When research involves significant risk of serious impairment, review
committees should be extraordinarily insistent on the justification of
the risk (looking usually to the likelihood of benefit to the subject--or,
in some rare cases, to the manifest voluntariness of the participation).

The Belmont Report

 Invalid Informed Consent

Valid informed consent requires:

• Disclosure of information on the objectives of
the research, benefits, risks, and alternatives.

• Understanding of this information by the

patient.

• Voluntary—uncoerced—consent.
 Invalid Informed Consent

Problems with disclosure of information

• Physicians do not provide appropriate or accurate information.

• Physicians stress and exaggerate the benefits while minimizing the

risks of research participation.
 Invalid Informed Consent
“Consent forms are often very deficient and they over promise. They
make Phase I studies sound like the cure for your cancer.”

LeRoy Walters, The New York Times

 Invalid Informed Consent

Problems with patient understanding.

• Because they are terminally ill, patients cannot

understand the true objectives, benefits and risks
of Phase I research. Their understanding is
clouded by their physical state and their hope for a
cure.

• What clear thinking patient would opt to take toxic

drugs rather than receive palliative care and
comfort measures at the end of life?
 Invalid Informed Consent

• Because terminally ill patients are not given proper

information by their physicians, because they cannot
understand the information they are given, and
because they are vulnerable, they cannot provide
valid informed consent.
 Invalid Informed Consent

• Vulnerable populations that cannot provide

informed consent are protected through special
safeguards.

• These safeguards preclude research that provides

no benefits to patients if it also includes greater
than minimal risks or a marginal increment over
minimal risks.
Responses to Criticisms
 Risk-Benefit Ratio
• Is it ethical to conduct Phase I research when there are no expected
benefits to enrolled subjects?

• What types of Phase I research is being done?

• What are the actual risks and benefits of Phase I oncology research
historically and today?
 Risk-Benefit Ratio

• It can be ethical to conduct research without

benefits to patients if the knowledge-risk ratio is
favorable.

• A favorable knowledge-risk ratio requires that the

knowledge gained is socially valuable.
 Risk-Benefit Ratio
• Conducting early Phase I oncology research in which the drug doses
are too low, may not be socially valuable in terms of knowledge about
safety, toxicity and the MTD.

• Ironically, having a favorable knowledge-risk ratio may require more

risk because only then is procuring knowledge possible.
 Risk-Benefit Ratio

This thinking argues for use of the more innovative Phase I designs
such as:
• Intrapatient dose escalation
• Accelerating dose escalation
• Requiring 1 patient rather than 3 at low doses
 Risk-Benefit Ratio
• Yesterday’s Phase I is not today’s Phase I.

• Nature of Phase I oncology studies have changed. They are no longer

only trials of “first in man” chemotherapeutic agents.
 Risk-Benefit Ratio

Review of CTEP Phase I data from 1991-2002

• 21% single investigational chemotherapeutic agent.

• 42% single investigational agent of any kind.

• 55% multiple investigational agents.

• 45% include at least one proven agent.

 Risk-Benefit Ratio
Estey et al. (1986)

Reviewing 187 trials involving 54 drugs and 6,447 patients between

1974-1982.

• Complete Responses: 0.7%

• Partial Responses: 3.5%

 Risk-Benefit Ratio
Decoster et al. (1990)

Reviewing 211 trials involving 87 drugs and 6,639 patients between

1972-1987.

• Complete Responses: 0.3%

• Partial Responses: 4.2%

• Toxic deaths: 0.5%

 Risk-Benefit Ratio
CTEP Database

• 460 trials between 1991 and 2002

• 10,402 patients for response
• 11,935 patients for toxicity
 Risk-Benefit Ratio
RR CR SD
Overall (460 agents) 10.6% 3.1% 34.1%
1 Invest Chemo Agent 4.4% 1.5% 40.8%
(20%)
Multiple Invest Chemo 11.7% 1.5% 27.5%
Agent (2.6%)
Approved and Invest 16.4% 5.6% 31.3%
Chemo Agents (19%)
1 Invest Signal Transd. 3.2% 0.7% 39.3%
Agent (11%)
 Risk-Benefit Ratio
Death Grade IV
Toxicity
Total (11,935) 0.49% 14.3%
1 Invest Chemo Agent 0.57% 15.0%
(2,621)
Approved and Invest 0.77% 14.5%
Chemo Agent (2,594)
1 Invest. Sign Transd 0.19% 13.0%
(1,565)
 Risk-Benefit Ratio

•211 Phase I studies published in 2002

•6,008 evaluable for toxicity
•5,362 evaluable for response

CR PR SD Deaths
3.8% 15.2% 23.0% 1.1%
 Risk-Benefit Ratio

Overall response rates may hide important

response data:

Response Rate # of drugs % of drugs

>15% 4 4.5%
10-15% 5 5.7%
5-10% 18 21%

Only 39% had no objective responses

 Risk-Benefit Ratio
Some remarkable therapeutic benefits in Phase I oncology trials

• Platinum had >50% response rate in testicular cancer and 25% long
term survival.

• Gleevac had >90% response rate in CML.

 Risk-Benefit Ratio
• Some data suggest that enrolling in Phase I research is beneficial to the
quality-of-life of patients.

• Patients in Phase I had stable QOL and performance status over 1

course of therapy whereas similar patients receiving supportive care
had lower levels of QOL.
 Risk-Benefit Ratio
• Risks are not as bad as implied.

• 0.7% risk of death for a terminally ill patient may not be very high.

• It would be good to have more data on the risks of other side effects
and morbidity rates.
 Risk-Benefit Ratio
• Benefits may be greater than implied.

• Many Phase I drugs trials have had >15% response rates and at least 2
notable cases have provided substantial therapeutic responses
including cures.

• QOL may be better on a Phase I trial.

 Informed Consent

Can terminally ill patients provide informed consent?

• Do Phase I researchers misinform patients?

• Do Phase I informed consent documents misinform?
• Do terminally ill patients misunderstand information about
Phase I research?
• Are terminally ill patients under a therapeutic
misconception?
• Are terminally ill patients vulnerable?
Do Phase I Researchers
Misinform Patients?
 Do Physicians Misinform?
Tomamichel et al. (1995)

• Recorded informed consent interactions for 32 patients.

• Quantitative analysis indicated that 3 major information points were

communicated in almost 80% of cases.
• Use of indirect patient responses was not as good.
 Do Physicians Misinform?
Daugherty et al. (1995)

18 Phase I oncologists at U of Chicago

• 1-2 months added survival: 10%
• Complete and partial response: 15%
• Complete response: 1%
• Life-threatening toxicity: 10%
• Death: 5%
 Do Physicians Misinform?

Meropol et al. (2003)

48 physicians and 328 patients considering Phase I

Discussed with Patients Physicians Patients

Possible side effects 92% 78%
Possible risks 92% 73%
Possible benefits 90% 79%
Change in length of life 60% 29%
 Do Physicians Misinform?

• Benefit from experimental therapy: 15%

• Adverse events experimental therapy: 10%

 Do Physicians Misinform?
• Limited data suggests physicians do not misinform patients and if they
do misinform they tend to over-estimate risks more than benefits.
Do Phase I Informed Consent Forms
Misinform?
 Do Forms Misinform?
Data from a review of 272 Phase I informed consent documents from
1999.

• Only 29% of all Phase I oncology trials involve a previously untested

drug in classic dose escalation design.

• 40% of Phase I trails had a therapeutic element. For instance, adding a

new drug to a known effective drug.
 Do Forms Misinform?
• 92% mention safety, dose determination, or toxicity as the purpose of
the trial.

• 99% mention that the study is research or an experiment with most of

these being prominent or highly prominent in the informed consent
form.
 Do Forms Misinform?
• 6% explicitly mention that the research is not therapeutic.

• 96% refer to the chemotherapy agent as treatment or therapy, without

any modifier such as “experimental”.
 Do Forms Misinform?
• Median length of risk and benefit sections
• Risk: 35 lines
• Benefit: 4 lines

• 67% mention death as a possible risk

• 33% mention death more than once
• 83% mention possibility of serious harms
 Do Forms Misinform?

• One of 272 forms mention benefits will definitely

accrue to subjects.

• Mentioned as possible benefits

• Cure: 5%
• Life prolongation: 20%
• Tumor shrinkage: 36%
• Generalizable knowledge: 68%
 Do Forms Misinform?

• 96% have separate alternatives section

• Mentioned as alternatives
• Palliative care: 56%
• Standard therapy: 88%
• No treatment: 65%
• Other experimental therapy: 52%
• Hospice: <1%
 Do Forms Misinform?
While the documents are not perfect and can be improved, it is hard
to say that informed consent documents:

• Over promise benefits and minimize risks

• Disguise the nature of the trial or that it is research

• Promise cure
Do Terminally Ill Patients Misunderstand
Information about Phase I Research?
 Do Patients Misunderstand?
Decoster et al. (1990)

• 91% of patients on Phase I trials had prior therapy:

• 50% chemotherapy alone

• 25% chemotherapy and radiation therapy
• 11% radiation therapy alone
 Do Patients Misunderstand?

• Daugherty et al. (2000)

• 144 Phase I patients

57% male
88% Caucasian
59 median age (26-82)
57% some college or more
 Are Patients Vulnerable?

• Meropol et al. (2003)

•328 patients considering Phase I trials

ALL Enroll Decline

White 86% 85% 90%
Some College 64% 64% 68%
 Do Patients Misunderstand?
• Daugherty et al. (2000)

Recall signing consent form: 100%

Recall explanation of study as research: 98%
Recall explanation of risks and side effects: 97%
Recall at least 1 specific side effect: 100%
Felt well informed: 96%

Quality of the information transfer was associated with higher

education.
 Do Patients Misunderstand?

Joffe et al. (2001)

Mailed survey of 207 Phase I, II, and III cancer

patients.

50 in Phase I studies, but not distinguished in data

analysis.
 Do Patients Misunderstand?

Joffe et al. (2001)

• 84% read the consent form carefully

• 87% had enough time to learn about the trial
• 93% sufficient time to ask questions
• 48% consent discussion last over 1 hour
• 44% consulted an outside physician
 Do Patients Misunderstand?
• Almost all patients participating in Phase I studies feel well informed
and are satisfied by the informed consent process:

Study # of Patients % Satisfied

Daugherty 144 96%
Tomamichel 31 96%
Joffe 207 90%
 Do Terminally Ill Patients Have a
Therapeutic Misconception about Phase I Trials?
 Therapeutic Misconception?

Study # Subjects Results

Yoder 37 70% to get best care

85% shrink tumor
Tomamichel 31 59% medical benefit
Cheng 30 60% medical benefit
 Therapeutic Misconception?
• Daugherty et al. (2000)

Patients views of purpose of Phase I

• Anticancer Response: 61%

• Toxicity Determination: 27%
• Combination: 8%
 Therapeutic Misconception?
Meropol et al. (2003)

Maximum Benefit of Experimental Therapy

37% of studies only investigational agents

• Totally cure: 39%

• Reduce cancer: 26%
• Control cancer: 30%
• Improve symptoms: 3%
• Nothing: 2%
 Therapeutic Misconception?

Joffe et al. (2001)

• 75% reported that the main reason for trials was to

improve treatment of future patients

• 71% there may not be direct medical benefit to me

• 48% report treatments and procedures in the trial are

standard for their cancer
Are Terminally Ill Patients Vulnerable?
 Are Patients Vulnerable?

Vulnerable population is a technical term meaning

those patients who for reasons of

• mental incapacity
• physical environment, such as prison
• history of discrimination and powerlessness, such as
African-Americans

cannot defend their own interests through

informed consent and need added protections.
 Are Patients Vulnerable?
The characteristics of patients on Phase I research
trials are:

• Sex: 57% male

• Age: Mid 50s.
• Race: 88% white
• Education: 2/3 have some college education
• Hair: All are bald

This is not the socio-demographic picture of a

vulnerable population.
Why Are Terminally Ill Patients
Enrolling in Phase I Studies?
 Why?

• They deny or refuse to acknowledge death

• They want to go out fighting
• They know their options
• Nothing—or almost nothing—would preclude
them from enrolling
 Agrawal Study

• Goal is 250 Phase I patients at 5 centers

• NIH, Fox Chase, MD Anderson, San Antonio,
Northwestern

• Survey on the day of decision-making with

personality profile.

• 148 patients interviewed so far—2nd largest study

of Phase I trials.
 Go Out Fighting
“We who are struggling to escape cancer do not, obviously, want to
die of it. We do prefer death in the struggle to life under cancer’s
untender rule. The enemy is not pain or even death, which will come
for us in any eventuality. The enemy is cancer, and we want it
defeated and destroyed…”
 Go Out Fighting

This is how I wanted to die—not a suicide and not

passively, but eagerly in the struggle.

George Zimmer
Phase I patient, University of Chicago
 Nothing Will Dissuade Them
Would this side effect prevent you from
enrolling in the Phase I research trial?

Losing hair 5%
Gaining 20 pounds 6%
10% chance of dying from side effect 9%
Drugs that don’t kill cancer cells 1%
Drugs that temporarily undermine 24%
ability to think
 The Problem
There is one major problem with Phase I trials:

Communication about life expectancy.

 The Problem
• Only 24% of patients “discussed life expectancy with their oncologist”
a moderate amount or a lot.

• Only 14% were told a specific time frame.

 The Problem
This was problematic for some patients.

• “He wouldn’t answer the question I asked [about survival].”

• “I tried to discuss it [life expectancy] but he will not tell me ‘you have a
year or less.’”
 The Problem

• Obviously, discussing life expectancy for someone who

has less than 1 year to live is not easy or pleasant. We all
avoid it.

• But it is necessary for some patients.

• Ironically, it might increase enrollment in Phase I trials

since people are enrolling even when they think they
have long life expectancies.
• 8 Principles for ethics research
• Phase I oncology trials are claimed to be unethical because they are
deficient in 2 principles
• Risk Benefit ratio
• Informed consent

• Studies of risks and informed consent suggest these worries are not as
serious as critics suggest.
 Conclusions
• Risk-benefit ratio for Phase I trials has changed because the type of
Phase I trials have changed.

• Patients who enroll

• Have sufficient information disclosed to them.
• Are satisfied by the amount of disclosure.
• Understand most of the information disclosed.
 Conclusions
• Like Geraldine, patients who enroll in Phase I trials want to fight their
cancer and almost nothing will dissuade them.

• Oncologists need training to provide better information about life

expectancy. But this may only increase enrollment in Phase I trials.
 Course Directors

Dr. Lisa M. Cordes Dr. William Douglas Figg, Sr

PharmD, BCACP, BCOP PharmD, MBA