Review of Concepts |
High Risk FL
Ethical Principles of Research (Belmont report)
Research: an advocate's perspectives |
Concept Review Tips/worksheet
It's a learning journey
Clinical research advocates - helping
patients to think more like scientists
and scientist to think more like patients, who are the primary
stakeholders in clinical research
Research advocates engage
scientists, review research priorities, concepts,
protocols and informed consent documents. As
representatives of the primary stakeholders in clinical
research, our role is to provide the patient perspective - such
as how the community is likely to perceive the research, the
burden of research-related tests, the feasibility of accrual,
and the importance of the study questions to patients.
We are people
from all walks of life who wish to engage and help scientists to
carry out research in order to make progress against the disease
that afflicts us, or a loved one, and our community. We are experts about the
experience of treatments and what it is like to live with
the disease. While the overwhelming majority of
researchers are themselves sincere advocates for patients, we
can provide unique perspectives and ideas that can enhance the
quality of the study design and the feasibility for timely
accrual. Advocate involvement and vetting of clinical
research also helps to establish public trust in research, which
Because many aspects of clinical research
are technical, it's important for research advocates to "know what we
don't know," to be good students of clinical science, and to seek mentors to consult when we are uncertain
about a research issue. In many cases, the QUESTIONS we
ask ... will be much more effective at influencing outcomes at
scientific meetings than
declaring a firmly-held opinion.
To achieve standing among experts
in the field - to be heard and to influence the outcomes of
discussions - advocates should be good
students of the following:
The natural history of the
disease - its expected clinical course and who it tends to
The standard of care or best
practice for the disease - the context against which study
protocols emerge and the need for improved therapies are
(clinical study design) - what types of studies are needed
to provide reliable (reproducible) information to advance
clinical practice or gain understanding of the biology of
the disease in order to guide clinical science.
The history of drug development and regulatory
review is very helpful - to provide an understanding of endpoints
chosen to measure outcomes in the tests of clinical
Ethical principles of
research, such as respect for persons
The informed consent process and
documents for the
purpose of helping the patient who is considering a trial to make an
Research advocate represent the
patient community. Therefore it's important for
advocates to engage our communities to understand their needs,
concerns, and perceptions. We are liaisons - who can help
explain the science and study rationales to the community, and
explain the perceptions and concerns of the patient to the
It's important for advocates and
scientists alike to keep an OPEN MIND.
We should be cautious about vigorously promoting a particular
approach to research (having an agenda) based on our own
circumstances and experiences, unless it is one that is widely
shared by the community or supported in the medical literature.
Consulting our mentors prior to making science or study design
proposals is essential to do before making such
Checklist for Advocates
when Reviewing Study
Concepts and Protocols
Also see PDF checklist that is more complete as of this writing:
Building on recommendations of seasoned research advocates
- participants in the cooperative groups and at AACR / ASCO events.
Scientific rationale for choosing the
study drug or protocol - is it strong?
Review literature then
inquire if needed:
Why made you choose the particular drug you’re
If there were no constraints, which other drugs
(experimental or approved) or combinations might you prefer
How might you overcome the constraints?
Study questions - relevance to patient
needs and goals?
What is the therapeutic goal of
therapy that can reasonably be expected?
What will be the participants expectation after reading the
Is the study question important to
What is the expected impact of the
treatment protocol and procedures on quality of life?
Is the treatment period longer than regular care? If so, will you
measure for impacts on quality of life?
Randomized trials - common issues:
Is there an effective therapy to compare
the study protocol to?
If not, could a larger single-arm study answer
the question reliably?
Is there genuine uncertainty about relative
risks and benefits for both arms of a randomized trial?
Is there a widely held perception that one or the other approach is better,
even if not proven definitively?
Do the compared protocols have similar, or
very different, toxicity profiles and risks?
Can a crossover option be provided for
participants who have toxicities or fail to benefit from the study or
control protocol - based on interim scans or observation?
Will Quality of life measures
be taken to compare the clinical impacts of the compared
Patient-reported outcomes and measures will be important for
patients - especially when other efficacy and toxicity
endpoints are found to be similar in a controlled study.
Justice (Belmont principle) - patient selection /
Do the eligibility criteria exclude large
segments of the patient community?
Can the eligibility be modified to make sure the findings are
generalizable to the patients in need?
How rapidly do you anticipate accruing
Would you prefer to accrue more rapidly? If so, what might you do?
What would be lost or gained by changing the eligibility criteria?
What could be gained by making your trial more inclusive (e.g.,
including patients with different tumor types, at different stages, and/or
with different treatment histories)
or less inclusive (e.g., restricting it to patients who have a
particular bio-marker and/or with fewer previous treatments)?
Relevance of study question when the study is
complete and the data is mature?
When do you anticipate completing your trial?
Given other ongoing work in your field, how likely is the result to be
Respect for persons (Belmont principle):
Feasibility - is study protocol attractive to patients?
What other trials or regular treatments
might be more attractive for eligible patients?
Does this suggest any ways you might modify your trial?
Will you list these alternatives specifically in the informed consent?
Do no harm - (beneficence)
What are the procedures (biopsies, blood
sticks, imaging) needed for the study that may impact accrual in the
How do the procedures needed for the study
compare (in number and by risk) to what the patient would receive with
If a patient does not do well while in your
study (e.g., has unacceptable toxicity, has disease progression),
what will you offer him/her (e.g., crossover to different treatment arm)?
If a patient is doing well at the conclusion of your study, what will you
offer him/her (e.g., continued access to drug)?
If you find that you are not accruing at the
rate you planned, what actions will you take?
How likely are you to recruit minority and
other medically underserved patients?
What can you do to increase your recruitment of these patients?
Brainstorm all of the likely and less likely
outcomes of your study.
For each, list the type of follow-up (e.g., next study) you would do.
Are there any outcomes that will leave you
unsure what to do next? If so, is there a way to change your design to
reduce or eliminate the likelihood of that potential outcome?
Brainstorm all of the things you can think of
that might go “wrong.” For each, list what you will do if the problem
occurs? Are there ways to design the study to reduce or eliminate the risk
of these problems?
Draw a timeline (Day Calendar) of
interventions your patient will receive?
Is the burden reasonable to expect from a patient as sick as the likely
patient in your study? Are there ways to minimize the number of visits to
the clinic (e.g., combine visits for diagnostic tests and treatments)?
Are there data that would be relatively easy
(and non-onerous to patients) to collect while you are conducting this study
that might be useful in the future (e.g., biopsies, blood, QOL measures)?
Are there collaborators that you could include to make use of such data?
Consent -- Checklist
Essential elements of Informed Consent
[Code of Federal Regulations]
PROTECTION OF HUMAN SUBJECTS
Basic elements of informed consent. In seeking informed consent, the
following information shall be provided to each subject:
(1) A statement that study involves research,
- an explanation of the purposes of the research and the expected
duration of the subject's participation,
- a description of the procedures to be followed,
- and identification of any procedures which are experimental.
(2) A description of any reasonably foreseeable risks or discomforts
to the subject.
(3) A description of any benefits to the subject or to others
which may reasonably be expected from the research.
(4) A disclosure of
appropriate alternative procedures or courses of
treatment, if any, that might be advantageous to the subject.
(5) A statement describing the extent, if any, to which
confidentiality of records identifying the subject will be
maintained and that notes the possibility that the Food and Drug
Administration may inspect the records.
(6) For research involving
more than minimal risk, an explanation as to
whether any compensation and an explanation as to whether any
medical treatments are available if injury occurs and, if so, what they
consist of, or where further information may be obtained.
(7) An explanation of whom to contact for answers
questions about the research and research subjects' rights, and whom to
contact in the event of a research-related injury to the subject.
(8) A statement that participation is voluntary, that
to participate will involve no penalty or loss of benefits to which
the subject is otherwise entitled, and that the subject may discontinue
participation at any time without penalty or loss of benefits to which
the subject is otherwise entitled.
See for additional information:
Illustrations should be
provided to present complex information
Day calendar showing what
they patients can expect
Labeled as regular
vs. investigational procedure
therapeutic vs. non-therapeutic
Labeled as guiding
care of participant vs. gaining knowledge for future
Background and Resources
Sources of Bias and Science-based
Methods to Minimize
End Points and United States Food and Drug
Approval of Oncology Drugs By John R. Johnson, Grant Williams, and Richard
Pazdur - FDA
Design of Phase I
Recommendations of the Clinical Trial Design Task Force of
the NCI Steering C.
Eliminating Bias in
Randomized Controlled Trials:
Importance of Allocation Concealment and Masking
Bias in randomized
NCTN 2014 Working Group
Report on Cooperative Group Trials
This report describes strengths and weaknesses of NCTN
studies by disease type (portfolio)
NEJM - Perspective: Expediting Drug
The FDA's New “Breakthrough Therapy” Designation
FDA Patient Representative Workshop - videos available for
Identifying Your Biases
All people develop
attitudes, preferences and biases. However, in order
to be an effective advocate, you must be able to recognize
your own attitudes, preferences, and biases. If you
don't your attitudes are likely to interfere with your
judgment. You could take positions which reflect your
biases, rather than the choices of the people for whom you
advocate. You may interpret the actions of others
cynically, or naively, and thereby lose your ability to work
effectively for the interests of others.
Informed Consent and Concept
CTEP forms for advocates and
Informed Consent Template for Adult
Simplification of Informed Consent Documents
Purpose of the Study - The purpose of this research
study is to find out whether adding the drug XYZ to a
commonly-used chemotherapy is better at preventing your
cancer from coming back than the commonly-used chemotherapy
Consent, at-a-Glance, compiled
Programs (CARRA, FDA Patient
consultants programs, NCI Director's Liaison, IRB, etc.)
FDA Advisory Committee
- Patient Representative program
Comment on Proposed Regulations and Submit
any citizen may submit a petition on any matter
of concern under the jurisdiction of FDA
Trial Design and Participation Consulting with
Patients, the FDA, Drug Sponsors, the NCI, and community
physicians. Establishing credibility through hard work and financial independence.
obstacles to participation in clinical trials
Biospecimen issues and resources
Primers on clinical research
The Ethical Principals of the Belmont Report
Institutional Review Board Member
Recommended book -
Principles of Clinical research based on the
Respect for persons (to insure self-determination)
autonomy, informed choice, voluntary, non-coercive, protect vulnerable,
privacy and confidentiality
Beneficence (to protect well-being of subjects)
appropriate risk/benefit -- do not harm; maximize possible benefits and
minimize possible harms
Justice (distribution of risk should be borne equally)
examine the characteristics of study population, ease of availability to
participation, not exclude classes of individual
• The principle
of respect for persons includes two separate moral requirements:
1) the requirement to acknowledge autonomy and 2_ the requirement to
protect those with diminished autonomy” (The Belmont Report)
In practice, this means that individuals have a right to decide for
themselves whether to participate in research. You may not use
information about people without first getting their informed
consent. Special care must be taken with people who are unable to
understand or who are particularly susceptible to coercion.
Two general rules apply:
(1) do not harm and
(2) maximize possible benefits and minimize possible harms.” (The
In practice, this means that it is not OK to use people for research
unless the research is likely to have some benefit. Furthermore,
this benefit must outweigh the risks.
Justice requires that people be treated fairly. Researchers should
not take from research participants without giving back:
“For example, the selection of research subjects needs to be
scrutinized in order to determine whether some classes (e.g.,
welfare patients, particular racial and ethnic minorities, or
persons confined to institutions) are being systematically selected
simply because of their easy availability, their compromised
position, or their manipulability, rather than for reasons directly
related to the problem being studied.
Whenever research supported by public funds leads to the development
of therapeutic devices and procedures, justice demands both that
these not provide advantages only to those who can afford them
and that such research should not unduly involve persons from
groups unlikely to be among the beneficiaries of subsequent
applications of the research.”
Ways to measure and compare outcomes, clinical benefit, in clinical
"For many centuries doctors used leeches and lancets
to relieve patients of their blood.
They KNEW bloodletting worked. EVERYBODY said it did.
When you had a fever and the doctor bled you, you got
EVERYONE knew of a friend or relative who had been at
death’s door until bloodletting cured him. Doctors could
recount thousands of successful cases."
When Laypersons Give Medical Advice
The lesson from history described above teaches us that the
clinical observations of medical professionals cannot be relied
upon when judging the efficacy of treatments. Scientific
methods are needed ... and have been the foundation of modern
The most common purpose of clinical trials is to test a
study protocol in order to judge if it will provide meaningful
clinical benefit - compared to the natural course of the disease
or the disease treated differently. Clinical benefit
from a treatment is defined as an improvement in survival or
quality of life. It can be very challenging to demonstrate
that a new treatment is an improvement over existing approaches.
For example the increase in response rate might be offset by
impacts on quality of life or late toxicities. Comparing
survival is the most objective way to compare outcomes ... but
this requires large studies to account for differences in
patient and disease characteristics - and, particularly for the
indolent lymphomas, the influence of the tested treatments on
response to subsequent therapies.
Background for new advocates:
Individual outcomes (even validated case reports) cannot be
used as evidence of clinical benefit for the patient or
others - because we cannot know how an individual would have
done had they approached it differently - or if that
patient's disease or risk factors are very much like other
So to judge how likely a new treatment will help others often requires
controlled trials on large groups of patients with the same
diagnosis, and similar risk factors. The most
objective evidence of how treatments compare will come from
large studies that randomly assign patients to the different
treatments to assure that the risk factors are balanced in
the compared groups.
Improved methods for evaluating the underlying biology of
lymphoma will reveal new subtypes that were formerly
considered one disease (such as Germinal B-Cell versus
Activated B-Cell Diffuse Large B-cell Lymphoma).
So we can expect that patient selection for trials will
increasingly be based on new tests that identify these
subtypes -- instead of doing "all-comer" trials and that the
increasing number of subtypes will increase the challenge of
carrying out sufficiently powered clinical trials.
Problems with Testimonials AND
claims and data
Demonstrating in controlled clinical trials
that a treatment improves overall survival is the most direct
evidence that the treatment provides meaningful clinical
benefit - as a difference in overall survival accounts for all
effects of the treatments - good and bad, measured and not
measured. When two or more treatments provide the
same or unknown survival benefit then the costs, and anticipated
impacts on quality of life can determine which is superior.
... However, there is a major issues with the
survival endpoint, as it's not ethical to wait and see which
approach to treatment improves the survival of two groups of
patients. Other treatments will be given to the patients
at relapse, which confounds assessment of the survival endpoint.
So we need other ways to judge if a therapy reasonably predicts
improved survival. These measures are called surrogate
Surrogate endpoints are like the parts of the
elephant touched by the
six blind men of Indostan
- each sensation reveals a different aspect of the elephant -
the toe, the ear, the trunk, but not the whole picture.
The surrogate endpoints commonly used by
investigators to measure outcomes in clinical trials are: tumor
response rates, relapse rates, progression events, side effects
rates, and the incidence of death. The events are counted
and plotted over time to see how often they occur and when -
relative to the beginning or the end of treatment - or relative
to the dose of a study drug in phase I testing.
The purpose of measuring endpoints is to
compare the effects of the study drug - good and bad, on the
patient or the disease. Quality of life endpoints measure
effects on the person - reported by the persons. Disease
event endpoints measure effects on the disease - reported by
Must be weighed against the toxicities and risks of the
compared to the risk of the disease untreated or treated
These terms are often used to evaluate and compare
responses to therapies (outcomes) in clinical studies. They do not
measure or predict individual outcomes, but are used to show how
effective the treatment was for a given group of patients in a
specific time interval.
Survival or Overall Survival (OS):
A measures of the
number of patient who are still alive following treatment in a fixed
Event free survival (EFS):
A measure of the number of patients who are still alive and have not
had a relapse (the event) following treatment in a fixed time
interval. For example: After 84 month the actuarial
survival rate was 93.1% and event-free survival rate was 87.3% for a
Time to Progression
(TTP) is a measure used to estimate the response to
treatment, generally in a clinical trial setting. As such it is
often called an endpoint. It goes something like this:
You get a baseline scan, usually CT, before
treatment to measure tumor burden. A second CT after treatment measures the response, generally
as a % of decrease in tumor burden (50% or greater being a Partial Response, and a CR indicating a Complete Response.)
From that point the time interval between the response to treatment and the time the disease starts to show evidence of growing (or recurring if a CR), is Time To Progression. Of course how often CTs are taken can affect this measure greatly, so TTP can only be an
Progression free survival (PFS)
measures time to progression, relapse, and to death from any
cause. The rationale for including "death from any
cause" - even if not apparently related to the disease or
treatment - is that it's not always possible to know what's related;
and accidental or unrelated causes will balance out when comparing
groups treated with different protocols.
Disease Free Interval
is similar to
Time To Progression, but it differs in that it only relates to complete responses (CRs), because
"free" indicates no disease measurable. So only a person who has had a CR can be among those measured for disease free
interval; for partial responders this term does not apply.
Patient reported outcomes (PRO)
captured the burden of the disease or treatments directly from
the patient - outcomes that cannot be
identified with standard tests, such as blood tests or imaging
Low versus High-Risk Lymphoma
How much risk is acceptable for treatment (or in a clinical
depend on the risk of the lymphoma and this can vary in the same
The following charts show different survival plots from time
of progression after R-CHOP – showing clearly that early
progression of disease (POD of less than 1 year) is worse in
respect to OS than late POD). The red line in each chart
shows the expected survival of the age-related normal
population. The dark lines with hatches show FL patients.
Note that the two charts on the left show no difference from the
expected survival of the normal population (red and dark lines
overlap) when the Event Free Survival (EFS12) for FL patients
after R-CHOP is 12 months or more.
Contrast this with the two charts on the right side, where the
red and dark lines separate in patients who did not achieve
Evaluating Patient Reported Outcomes
(PROs) -- gaining momentum
PROs may be especially
important to capture for protocols that require long periods of
treatment - maintenance. When provided prior to treatment, the
patient's report serves as the control when assessing
treatment-related outcomes that affect quality of life - such as
fatigue or pain.
The Symptom Management and Health-related
Quality of Life (SxQoL) Steering Committee has produced a number of
webinars to assist investigators in Concept Design and using PROs in
clinical Trials. These webinars are listed below and are live on
the NCI Division of Cancer Prevention Website:
NCI Shared Resources:
Symptom Management & Quality of Life
This video covers a variety of practical considerations for
developing a symptom management concept for clinical research.
Symptom Management & Quality of Life Concept Design
Practices for Integrating Patient Reported Outcomes in Oncology
The following webinar series is a collaboration of the
for Quality of Life Research and the
Institute. The videos in the series may be viewed
independently or sequentially in the order listed below.
David Cella, PhD presents
How to identify the PRO context for clinical trials and identify the
relevant PRO domains
Air date: 09/04/2014
Bryce B Reeve, PhD & Ethan M Basch, MD present
How to select the appropriate PRO measure
Air date: 09/03/2014
Madeleine King, PhD, Michelle Naughton, PhD, & Lari Wenzel, PhD
How to design a high quality study with PRO endpoints
Air date: 08/20/2014
Amylou Dueck, PhD & Diane Fairclough, DrPH present
How to develop the statistical plan and sample size calculation for
the PRO component of a clinical study
Air date: 08/19/2014
Carol M Moinpour, PhD & Andrew Bottomley, PhD present
How to assure data quality for PROs in oncology clinical trials
Air date: 09/04/2014
Michael Brundage MD & Melaine Calvert, PhD present
How to report PRO study findings from clinical trials
Air date: 08/19/2014
June 12: Dr. Sandra Mitchell,
Burden and Treatment Tolerability in Cancer Clinical Trials,
Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events
The key elements of the PRO-CTCAE measurement
system are exhibited, and the research challenges, gaps in knowledge,
and the issues that will need to be resolved to fully implement this new
approach are examined.