What is the purpose
of Research Advocacy? |
Perspectives on Trial Design
for Patients and Caregivers |
& Unity | Guidance for the NCI, the Industry, and the FDA
Research Funding and Insurance |
Perspectives - old and new
Advocacy Tools and Background
Perspective on Quality
of Life and Other Patient Reported Outcomes in Clinical Trials
on Industry versus Publicly-funded Research
Cuts in NCTN?
Learned in CLL |
Giving Tissue and Blood |
"Consent" for unspecified future use?
Why Research Advocacy?
To contribute and influence thought leaders and the design of
clinical studies, research advocates need to be ardent students
of the disease -- well-informed about regular practice and
with emerging approaches to treating the disease.
While it's possible for laypersons to achieve standing and be
heard by investigators, it takes a good amount of time and
study. Presently there are no formal "career" pathways to
follow. We advocates learn from other advocates, and by
doing it - pushed by our desire to advance progress against the
disease. We need also, like the best scientists, to know
what we do not know.
Patients and caregivers are the primary
stakeholders in clinical research as we must endure
disease and the inadequacies of existing therapies. As Chaya
once quipped: "We have the most skin in the game" (Not the
drug sponsor or shareholders, not the researchers or the clinical investigators).
are the ones recruited for testing of the investigational therapies,
which have unknown benefits and risks and which, in some cases, will ultimately be utilized by many of us. It
is we who lose the most when clinical trials do not meet enrollment
goals and fail to answer the study question ... a common and
tragic occurrence. We lose the most from siloed research
that fails to add to the body of scientific knowledge, or change
practice, or make future research more efficient.
Since we live with the disease and must
choose between therapeutic options, we can offer insights that will
not necessarily be recognized or raised by research colleagues, such as:
Anticipating how patients and referring physicians will
judge the protocol as a therapeutic decision (accrual)
Citing deficiencies in the informed consent document or process
The urgent need to standardize biospecimen capture, analysis,
and reporting (generalizability)
The need to make future studies more efficient by validating
surrogate markers for efficacy and safety.
The significance of the study question or events that are
measured (appropriate - non-ambiguous endpoints)
Concerns with the enrollment criteria that may become unnecessary
obstacles to enrollment or that may call into question how well the
study findings will apply to the population with the disease.
For my part, I wish to participate as a
research advocate because I feel that my
motivations, experiences, and training make me uniquely qualified to
provide the patient perspective in a positive way. I am a caregiver to my spouse; she is an
eighteen-year survivor of lymphoma. Together we have experienced the
uncertainties of treatment decisions, the disappointments and
successes - and have considered and participated in multiple
clinical trials and therefore have first-hand experience with the
clinical trial consent process.
I also serve the lymphoma patient community
on a daily basis, moderating support forums and updating our
non-profit website resource in response to patient questions, which
includes substantial information on clinical trials.
My experience includes providing support and
the review of studies for a broad range of lymphomas: low and high
risk, indolent and aggressive, including types that are managed
conservatively or that can have a rapid fatal clinical course if not
Background and Resources
Important for advocates:
FDA Patient Representative Workshop - videos available for each
NCTN 2014 Working Group Report on Cooperative Group
Must read for advocates and investigators
"Consent" for unspecified future use?
The source of the discussion is my talk on giving blood and
Specifically it’s on an ownership perspective, slide 9:
An advocate’s perspective on the “ownership” of patient-derived
• That researchers and medical institutions are stewards of
patient biospecimens (not owners)
• That the biospecimens that patient’s have taken risks to give
will be maintained and protected for optimal research use.
• That requests for biospecimen transfer (e.g., tissue blocks)
from one accredited institution to another should be granted
when the patient gives consent
Mine is not a particularly radical perspective but it appears to
go against the default policies of many institutions (based on
personal experiences and recent investigator comments).
Bioethicists have long cited the inadequacies of consent for
unspecified future use - it's just not possible for it to be
truly informed because we cannot anticipate future uses.
Further, the devastated patient receiving a cancer diagnosis is
not absorbing or considering all of the implications of a
Most commonly giving consent for unspecified future use is
optional and the consent document is boilerplate.
Institutional policies and consents seem remnants of a time when
the utility of patient samples was limited to in-house
laboratory studies. The choice was between discarding it as
waste material or using it in a lab to train future scientists
(which is a great use of it).
Today, the information in our cells (DNA) can potentially tell
researchers about our predispositions to disease ... not just
for ourselves but our families. Sometimes the findings – if
inappropriately linked to our clinical information (perhaps
still unlikely but increasingly possible) can be stigmatizing -
for example, our familial risk for alcoholism, drug addition,
dementia can be revealed with correlative research on our cells.
Correlative science by definition requires also annotation that
includes our clinical history in order to be useful - to be
correlated with something ... including our demographics (race,
age, sex, ... ) so it's important that future use of annotated
samples be de-identified (coded) to protect our confidentiality
and stored on IT systems with strong security measures in place.
Was this described in the consent you signed prior to surgery?
Probably you do not even remember. Probably it was boilerplate
and not specific to the systems of the institution you happened
to go to for surgery (by convenience, not choice).
So advocates of patients might ask:
* Are the institution's methods for protecting your privacy
* Do they de-identify the sample and clinical data adequately
(coding it) -- and who is the keeper of the key to that code?
* Do some institutions sell the clinically annotated samples to
a commercial third party?
What are their policies about the use of it? Do these align with
So I'm not a fan of unspecified future use even if the risks are
probably very small at this time. What are the indirect risks or
adverse impacts? How often do our samples expire due to
inadequate storage methods (rot on a shelf)? ... that could have
been used to learn something of values if done somewhere else.
With standards and new analysis tools our tissue and blood are
more likely to lead to insights about the disease. This
information will increasingly guide therapeutic decisions ...
including trial participation. Noting that our tumor samples
cannot always be resected (safely) a second time in every
So I'm inviting continued discussion on the need to reorient
medical institutions - to focus use of our "gifts" of blood and
tissue (and related consent) on disease-specific study and that
consent should be on a per-study basis if used otherwise. For
example, If the extra blood and tissue will be used for example
to help train lab technicians ... then consent for that in the
surgery consent document. (Using unidentifiable biospecimens for
training … the boilerplate consent text should be fine).
The justification and need to involve patients more fully in
consent has arrived .. and will only increase in the coming
years. Medical centers doing biospecimen-based research might
inform about the limits of that research (exploratory,
laboratory only, etc) or adopt standards for captures, storage,
analysis and protection of our associated clinical records (as
keepers of our personal information and clinical records, and
DNA). The institutions that take the lead may well attract
more patients – helping to offset the financial costs.
In keeping with the oft-cited goals of personalized medicine as
the root objective and justification for such research ... I am
advocating (again) for making available a portion of
appropriately stored extra tissue to guide participation in
trials based on markers of risk and response that can be
identified today with validated technologies. NCI MATCH seems an
exciting example of the information in our tissue guiding
promising research and giving hope to patients out of standard
options: Good science and good medicine.
Research Advocate, Lymphoma
Lessons Learned in CLL: the importance of cooperative
Re: Dr Sharman's Blog 2014:
Ibrutinib in 17P deleted CLL
Here we see an exemplary
example of a biomarker that spares patients from ineffective
therapy! If you have CLL with the 17p deletion (a specific
mutation) then chemo will not work for you. Better yet, patients
with this mutation respond great to a much less toxic targeted
So as Dr. Sharman, notes - folks with 17p CLL do not have to
try, suffer, and fail to benefit from chemo to use ibrutinib ...
big news indeed! How did researchers find this out?
According to an expert I consulted, the validation of the 17p
biomarker took thousands of patients and cooperative research by
investigators world-wide. It also helped that it's relatively
easy to get tumor samples for CLL - from the blood.
Finally, the commercial sponsors took advantage of the
cooperative group finding and demonstrated relatively easily
that ibrutinib addresses an unmet need in this high risk group.
So what drives progress is good science - validated biomarkers
that improve and guide (individualize) practice. Such progress
REQUIRES patient participation in trials and cooperative
research with biospecimens. There is NO other way. To make
additional progress against lymphoma ... patients must also take
Giving Tissue and Blood - an advocate's perspective
Meeting the information needs of patients, and advocating
for excellence in clinical science ... can work hand-in-hand.
Received positive feedback on this at Vail (Methods course in
clinical research) ... most importantly from the faculty in the
discussion group who recommended it be distributed widely.
Perspective on the Use of Quality of Life (QOL) and other
Patient-Reported Outcomes (PRO) in Clinical
There are two potential uses for
Patient-reported Outcomes (PROs) in
clinical trials and in regular practice.
first is to monitor the patients for significant changes in their
overall status that would not otherwise be captured.
2) The second is to
measure and compare patient reported outcomes as endpoints in a
clinical trial -- as a way to
measure the effects of treatment that otherwise would not be
accounted for by laboratory tests or scans.
The terms PRO and QOL are sometimes used interchangeably and
this seems to be a source of confusion and is perhaps contributing
to the slow adoption of these measures of clinical outcomes.
PROs might be thought of as way to capture information that is
specific to a
common symptom of the disease, or to
an anticipated side effect of the study drug. QOL instruments can also capture the patient's experience of pain or
fatigue, but can provide valuable information about the whole
patient (global changes) - such as changes to the patient's
sense of well-being.
An easy-to-use and score, standardized QOL
instrument should be incorporated into all trials:
monitor and improve patient safety
(e.g., test for need to reduce dose when indicators drop
identify patients in
(e.g., are in danger of dropping out for safety / financial /
social / physical / emotional
To compare populations across studies in a
(e.g., QOL scores were comparable) … and
To inform about outcome
that are important to patients, which are measured poorly in other ways
(e.g., pain, fatigue).
QOL and PRO endpoints can be informative even for small
single arm studies, because the
survey is started prior to treatment and the patient is therefore his or her own
That we are asking the patient about their
experience shows that we care about them and are committed to
following them carefully to identify needs and changes in their well
QOL endpoints may be particularly important to
capture when the duration of treatment is long (e.g., many months or
indefinitely until relapse) ... as a way to understand the
impact of the treatment (including financial toxicities) on the
As an endpoint there is the challenge of
accounting for the placebo effect (our expectations influencing
how we feel and what we report) and the influence of response to
treatment (the tumor is visibly shrinking or growing) on how we
In the future we might also use a
standardized QOL tool as we would any laboratory test to monitor
the patient for changes in perceptions about symptoms and side
effects that can only be self-reported and as a way of
monitoring for changes to overall quality of life - to guide in
the care of the patient, such as for the need for emotional,
social, or financial assistance.
See also Quality of Life
Perspectives on Clinical Trial Design
The need to make progress against cancers is
urgent and is dependent on the conduct and completion of
well-designed clinical trials. There is NO other way
Clinical trials must have the potential to
answer relevant clinical questions, while providing also a strong
therapeutic rational for participation. By this I mean that
study protocol (both if in a randomized allocation design) must have a potential to provide clinical
benefit roughly equivalent or superior to available standard
therapies, or the best supportive care.
Failing to meet the first requirement there
is no purpose in doing the study. Failing to meet the second we
have a high probability that the study will not complete enrollment,
which means that some patients will have been exposed to risks for no benefit to society. Further, the conduct of poorly
designed trials dilutes the pool of available participants, making
it more challenging for better-designed studies to complete
I have a traditional
views about clinical trial design. I fully endorse the importance
of randomized controls in many cases, and sufficient sample size in order to
objectively assess efficacy and risks; and in the selection of
eligible participants by criteria that reflect the population the
therapy is ultimately intended to serve.
I am keenly interested in the discovery and
validation of biomarkers that may be used as surrogates for clinical
benefit to accelerate the assessment of future therapeutics that may
help to individualize therapeutic decisions - helping patients to
avoid unproductive toxicities, which can decrease the range of
effective therapies that may be used later by the same patient.
I believe that the rationale for
participation needs to be considered early and throughout the design
process. Developing the rationale for a clinical
study as a therapeutic decision requires insights and knowledge of
best practice and the natural history of the disease in the various
clinical settings. While this challenging task is best carried out
by experts in the field, it must be communicated in an intelligible
way to the would-be participants in order to be judged a reasonable
alternative to standard therapies and to achieve a high level of
Finally, while I have received training in
the review of clinical trials from the FDA patient representatives
program and from independent work, I am aware that as a layperson I
will have gaps in my knowledge and therefore I will endeavor to
provide input mainly from the perspective of the patient – who has
the disease and is considering participation. Advocates
must be good students of the disease, how it is treated, and
also emerging investigational options.
Trial design - proposing the PCT as an alternative to the RCT
Perspective on industry- versus publicly-funded trials (DRAFT)
Patients (all of us eventually) depend on
industry AND publicly-sponsored trials
to reduce the burden of disease. It is NOT an either-or
as some politically-oriented folks would have us think.
There's considerable overlap
(cooperation) between industry - and taxpayer-funded
clinical research as each will involve testing of commercially owned
drugs - approved and investigational.
Patients depend on the
industry-sponsored trials to test new
drug products or new uses of approved drugs. Only the industry has the
resources and ownership rights needed to provide manufacturing and
This role is critical to ensure all patients have access to
the drugs that demonstrate efficacy and win FDA approval. The
testing of new drugs carries a very high financial risk (for
investors) as many such trials fail to win marketing approval - an
evaluation process that requires substantial time and sums of money.
The financial risks are mitigated by patent law - allowing the
company to have exclusive rights and to charge what the market will
bear - allowing the companies to realize very high profits if they
succeed. These benefits are provided to the
company by public consensus (arguably and ideally) in order to encourage the development of
better treatments ...in order to serve the public good.
Without financial incentives and ownership rights drug development would
not be done and patients would continue to die from medical
conditions that have the potential to be treated effectively, such as
demonstrated for HIV and many types of lymphoma.
The primary mission of any drug
company is to maximize profits; so there will be an inclination to
focus on trials that enhance that goal, and avoid sponsoring studies
(or providing the study drugs) if the study outcome puts their
for-profit mission at risk. The objective of maximizing
profits is not a sin, it is simply a
fact of life - the company's reason for being.
There is so much of critical importance to
patients to learn about how to use
approved drugs. Much of this is not typically of interest to industry
sponsors, such as how to identify the best dose and administration
schedule of an antibody drug (RESORT), or how to identify up front
which patents will benefit from the drug and who will experience
only unproductive toxicity.
Further, the scientific
insights and data gathered in publicly-funded
studies is more likely to be shared and published - such as tests
that may predict response to an approved treatment. Commercial entities
may also be reluctant to sponsor trials (or provide the study drug)
that compare their product to a competitor's in pick the winner
trials - or to study treatments for uncommon medical conditions that
have a low profit potential.
Commercial drug products are not invented in a
vacuum - the idea evolves or emerges from the larger body of
scientific knowledge - including discoveries of treatment targets
made by publicly-funded basic science. Commercial groups
certainly play a role in scientific discovery, but the body of
science is most accurately described as a public resource. Its validity and strength
depends on peer review, on standards for scientific methods,
on reporting to scientific journals, on regulatory review, and also very often on patient participation in clinical trials!
Virtually all publicly-funded therapeutic trials will require cooperation from the commercial
sponsor - because they legally own the drug (developed or purchased
it) and their study drug is not yet
approved. (So like we learned in the schoolyard, the kid who owns the ball has veto power about the
rules of the game.) So it's important to patients that we
can efficiently identify shared goals and
develop guidelines on the types of studies that are most appropriate for
public funding. Here we will propose a list of attributes and
invite comments and suggestions from visitors.
We can think of cooperative group research as
science … motivated to advance the common good, funded by the
common man (taxpayers); and industry-research as that which is
done for the purpose of generating a profit, funded by
shareholders from any part of the globe.
Study type / attribute
|Study drug tested for common disease for purpose of
winning market approval (registration trials)
||The study will get done anyway; public will not share in the
financial benefit. Public could benefit from
correlative science and assays but only if published and
|Study drug tested is part of induction and maintenance
(not compared to another study drug)
||A win-win situation for the company no matter which arm is superior;
it will get done anyway; larger public will not share in the
financial benefit. Public could benefit from
correlative science and assays but only if published and
|Study drug tested for orphan conditions or new subset of
a disease based on biology of the disease
low market / profit potential
|Compare approved protocols already used in clinical
practice when either is considered reasonable
||little industry incentive to compare effectiveness if
they are profiting
|Pick the winner of multiple study drugs by different
commercial sponsors to combine with approved agents
||little industry incentive to provide study drug unless
there is no other clear path to testing it.
|Study involves evaluating a novel test having the
potential to accelerate the evaluation other interventions
||potential to advance science and run other trials more
|Study drug tested in combination with approved protocol
without compelling science about mechanism of action
(synergy) or selecting patients
||exploratory; unlikely to advance the science
|Study of promising new or existing compound with no
interested or available commercial owner
|... more to come
|Notes from Publicly Funded Clinical Trials
and the Future of Cancer Care
Richard L. Schilsky, M.D.
Professor and Chief
Section of Hematology-Oncology
University of Chicago
Deputy Director, Comprehensive Cancer Center
Optimize Treatment (drug registration)
Create New Knowledge (expand market share)
Improve Public Health (create shareholder value)
Compare the effectiveness of various treatment options
Combine/compare drugs developed by different sponsors
Develop therapies for rare diseases
Address optimal dosing
Test multi-modality therapies such as radiation therapy in
combination with drugs
Identify patient and tumor subsets most likely to benefit
Study screening and prevention strategies
Focus on survivorship and quality of life
Publish negative results
Assess cost and cost-effectiveness
Provide “gold standard” databases for registry studies
Compare Treatments from Different Sponsors
“Comparative effectiveness research is the generation and
synthesis of evidence that compares the benefits and harms
of alternative methods to prevent, diagnose, treat and
monitor a clinical condition or to improve the delivery of
The purpose of CER is to assist consumers, clinicians,
purchasers and policy makers to make informed decisions that
will improve healthcare at both the individual and
Survival Comparing Laparoscopic-assisted Colectomy with Open
Rare Disease Treatments
Combine Treatment Modalities
Identify Patient Subsets
Testing protocols in patient subsets:
CALGB 9343: Impact of Breast RT in Older Women Receiving
Tackle practical problems:
Most people who are diagnosed with cancer are elderly
Most people who are on clinical trials of anti-cancer
therapy are not elderly
The risks and benefits of anti-cancer therapies in the
elderly is uncertain
Who Benefits from Adjuvant treatments
Survival Comparing Laparoscopic-assisted Colectomy with Open
Publish Negative Results
Assess Cost Effectiveness (for equivalent treatments)
Provide Gold Standard Databases
DFS According to Data Source
SEER-Medicare Analysis of RT Use in Older Women Following
Publication of C9343
Translational Science Infrastructure
correlative science infrastructure
Exploratory (Correlative) Biomarker Studies
BRAF Mutation is Prognostic in Stage III Colon Cancer: CALGB
PKC 412/FLT3 Mutation Analysis Co-Development CALGB 10603
Marker Validation Studies
Cooperative groups have the capacity to conduct many types
of biomarker studies, including formal validation trials
Publicly funded clinical trials are essential to:
directly compare drug treatments;
develop combined modality treatments;
study chemoprevention and rare diseases;
identify patient subsets;
study health outcomes, cost and cost-effectiveness
Creation of the National Clinical Trials Network
National Clinical Trials Network (NCTN) provides essential
infrastructure for publically funded trials in treatment,
control, screening, diagnosis, and prevention
NCTN provides a unified clinical and translational
infrastructure for the extramural cancer community:
investigators, patients, advocates, and industry
NCTN efficiently functions to answer critical questions not
well supported in a commercial environment
NCTN will eventually replace the program we have known as
the cooperative groups
Risks of Replacing the Cooperative Groups
Loss of institutional allegiance and cost sharing
Fewer publically funded trials
Loss of young investigator mentoring
Loss of competition to drive innovation
The NCTN becomes a research infrastructure but not a
Time will tell whether the NCTN is able to set new standards
of care for cancer patients
The future of cancer care depends on a robust, publically
funded clinical trials system!
Patient Advocacy Background and
A link to my advocacy CV
||Summary for Karl Schwartz
President and co-founder, Patients Against Lymphoma
Alliance Cooperative Group, Lymphoma Committee
FDA Advisory Committee
-Progress Review Group
-Biospecimen Best Practice Workshops
-Steering Committee - Lymphoma
-Centralized Institutional Review Board
Patient Advocate Faculty ASCO/AACR Workshop:
Methods in Clinical Cancer Research
Stand Up to Cancer, Joint Scientific Advisory Committee
Advocate Perspectives - old and new:
On Ownership of an
On Biomarkers - Draft: perspectives and resources
On Rising Healthcare Costs ...
Threatening Access to Quality Cancer Care
On Progression Free Survival:
Is it the Right
Endpoint for Judging the Clinical Benefit of Maintenance Rituxan
following First Therapy for Indolent Lymphoma?
One Advocate's perspective
On Finding & Evaluating Online
Medical & Support Information
Teleconference presentation for
Nurses and Social workers:
Sponsored by Lance Armstrong
Leukemia and Lymphoma Society, July 2009
Giving Tissue and Blood - an advocate's perspective
Interest, attitudes, and participation in
clinical trials among lymphoma patients with online access.
published: ASCO 2009:
Letter to FDA on Transparency initiative
Vaccines and Autism link:
It's easy to
confuse correlation with causation -
Tony L. Hines
On Progression Free Survival: Does
predict better survival in Follicular Lymphoma?
Reviews, Vaccine misinformation, Level of Evidence
On statistics for lymphoma subtypes (letter
to SEER) PAL
The SEER website has improved, but the utility of the
statistics for non-Hodgkin's lymphomas continue to suffer because
subtypes of the disease are not yet provided.
UPDATE FROM SEER:
On Biobank Best Practices:
Patient Perspectives on the
issue of transfer of tissue for clinical use –
particularly for use in translational clinical research - PDF
"we may not have fully considered that requests for
transfer of tissue for clinical use could many times be in
harmony with the ultimate objective of achieving “personalized
medicine,” and the oft-stated principle of “partnering
with patients” – particularly when used to determine
eligibility for clinical trials."
For Patients and Caregivers:
URGENCY & UNITY
For the NCI, the Industry, and the FDA
To help accelerate the development and evaluation
of investigational therapies for lymphomas.
attitudes towards trials: Report from our Lymphoma Patient Survey regarding
interest and participation in clinical
Adaptive Design Conference, July 2006, Washington
Goals with Meeting the Clinical Needs of the Participants
with narrative) PDF
Harmonizing Research Goals with
Meeting the Clinical Needs
of the Participants - Apr 2006 -
Presentation at Favrille Investigators Conference
Study Proposal: Combine molecular
profiling research with evaluating first-line use of
patient-specific idiotype cancer vaccines -
Update: No longer feasible given the disappointing outcomes from
vaccine phase III trials.
Advocating for Coordinated Immunotherapy Research
Eliminating Suffering and Death Due to Cancer by 2015: The Future of Cancer Research
Let's not forget Immunotherapy! - A letter to Dr. Von Eschenbach
"The patient is waiting"
- patient perspectives
on aspects of toxicity and the need for innovation -
an appeal for NBN in a
brochure format PDF
Ablation for lymphoma? PAL
trial design and participation - We consult with
Patients, the FDA, Drug Sponsors, the NCI, investigators, and
physicians. Our goal is to increase participation in order
to accelerate progress against the disease. How else?
Ablation for lymphoma? PAL
WHEN? Rationale for the National Biospecimen Network
There's an urgent need for new approaches and tools to accelerate
clinical research, such as the National Biospecimen Network.
One reason that even well-controlled studies fail to provide
definitive answers, it seems, is they are often unable to account
for underlying biological differences in the tumors and patients.
AND INSURANCE COVERAGE