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Ownership Issues
Ethics of Requiring Tissue Biopsy for Study Participants
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PubMed
From our perspective, creating a human bio-bank
- with high standards for uniform capture, annotation, storage,
analysis, and sharing of data - is essential to making progress against cancer.
Such a resource would be equivalent to the electric power infrastructure
as a driver for our economy. Consider the inefficiency if each company had to generate it's own electric
power in addition
to doing it's primary business. Imagine the confusion if
one State used AC and the other DC!
The Need for Harmonization in Bio-banking to
Realize the Potential of 21st Century Medicine
Dr.
Anna Barker, NCI PDF
"Biospecimens are materials from the human
body,
such as tissue, blood, plasma, and urine,
that can be used for cancer diagnosis and analysis." 27
Background
 The
National Biospecimen Network (NBN)
is a blueprint for progress that will create a national
bio-informatics bank that's accessible to all scientist.
"The
number one roadblock to our progress, as defined
at the think tank
Dialogues on Cancer (2002),
is the lack of availability of high quality, highly
characterized
human specimens for translational research."
Key components
(1)
Standardized capture, storage, and analysis of large numbers of annotated biospecimens
(tissue, blood, urine)
- so that research findings are comparable and the results are statistically
powered;
(2) Bio-Informatics software that can store the considerable amounts of
clinical and molecular data, linked to the tissue.
(3) Common data elements, so that
each research group is reporting and describing data using the same terminology.
(4) Data sharing, including publishing
of failed research, so discovery and validation of biomarkers can be
accelerated and resources can be deployed efficiently.
(5) Privacy protection - to inspire trust,
and ensure participation and continued public funding.
"Currently there are no standardized
procedures for
collecting, processing, storing, and distributing biospecimens." 27
.gif) |
caBIG: Power of Connection™ - Dr.
Barker provides a preview.
cabig.cancer.gov
The video explores the challenges of cancer research and how
caBIG™
will speed research discoveries and improve patient outcomes by
connecting
the cancer community.
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The big picture: the purpose of the study, the need for
reliable findings that can be translated into clinical practice, such
as biomarkers that predict response to treatment or toxicity.
I think John Donne's meditation applies well to clinical science, except that this ideal is rarely met. That is, the success or failure of a therapy is often a page torn out, which does not inform the science - the book we use to guide how to treat others.
" Ultimately, it may well be that the optimal treatment will be determined
by patient
clinical and biological characteristics." ~ Dr. Bruce Cheson
[4]
Why now?
FDA
... the vast majority of investigational products that enter clinical trials fail.
Often, product development programs must be abandoned after extensive investment of time
and resources. This high failure rate drives up costs, and developers are forced to use the profits from a decreasing number of successful products to subsidize a growing number of expensive failures.
[6]
 Gene expression largely determines how
tumor cells behave: how aggressively or
slowly they will grow, how resistant they are to dying, how and why they
respond to different treatments.
New technologies,
particularly
microarrays, can help to characterize gene expression in
malignant cells, allowing scientists to see what is wrong, and compare
one person's cancer to another's. For the first time in history
we can begin to see what we are trying to fix at a
fundamental level.
"The trick with
molecular targeting is that you have to be able to match the drug to
the patient. And until you understand how the drugs work, why
they work, and for whom they work, your results might not be as
remarkable as you would like for them to be. Once we understand
how to match the drug to the patient, I think we will
see many, many examples like imatinib [Gleevec]."
~ Dr. Brian
Druker, Howard Hughes Medical Institute [2]
The NBN approach to research starts with obtaining fresh frozen
tissue. Importantly, standardized methods of collecting and
testing tumor and normal tissue, open access to the tissue, test results, and associated clinical data will:
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Enable scientist to more rapidly identify the
gene expressions that distinguish normal from malignant cells and
assist in the "development of molecularly targeted therapies
that have specificity and potency for defined cancer types."
[1]
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Enable scientists to link clinical behavior (how
aggressive or indolent the cancer is likely to be) to gene
expression, and thus better advise patients about treatment
selection and timing. |
The variable clinical course of
patients given the same diagnosis stems, in part, from the
underlying molecular diversity among their tumors.
[1]
~ NBN blueprint
Note that the NBN should not represent a challenge to existing systems that are
functioning at high levels. Rather the NBN will incorporate the
"best practices" in existing systems of excellence.
Identifying, developing, and sharing standards for "best
practices" is a process and not an end. Thus, the NBN
blueprint will incorporate new ideas and innovations as they occur. It
will constantly improve and lead to innovations that will make a real
difference.
" As we move to consider these tumors by their genetic
abnormality (genotype) rather than their
cellular
appearance (phenotype), one converts the generalities of
leukemia, lymphoma, and
myeloma into hundreds of diseases
with distinct genetic causes, clinical manifestations,
and
drug responsiveness." 29
Briefly, the NBN is a blueprint for creating standards for how to:
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Obtain and store fresh frozen tissue
suitable for consistent molecular analysis |
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Apply disease-specific
cDNA microarrays in order to measure the expression level of
several thousand mRNA, simultaneously in biological tissue,
and conduct tests to validate the tools and the procedures |
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"Screen for genes
that are differentially expressed between normal and diseased
tissue in order to find novel targets for drug development or to
find new single-gene markers of clinical outcome." 10 |
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Protect donor
confidentially |
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Create an open and usable informatics
data system, which can provide open access to tissue and data - including longitudinal data (case data followed over
time) - thus enabling the correlation of gene profiles with treatment
outcomes |
Standards is not a "sexy" word, but adopting
standards is the key to
releasing the potential of technologies in any age. The Internet was made possible by adopting
standards (TCP/IP), as are the infrastructures we all take for granted:
electricity, telephone, plumbing, etc.
Shared and open access means small companies can compete
as well as large. It shifts the advantage from financial muscle to ideas and
creativity. Open access will create productive competition, and capital interest
will be sure to follow. Openness will replace the practice of restricting access in order to gain or
maintain a commercial advantage - buying up DNA patents, for example.
* Importantly, the data obtained from tissue is patient DNA. Thus,
it should not be "owned" by any group. The NBN blueprint cites this basic
fact.
The following is one example of how the NBN approach
can
foster more rapid approval of new drugs. It should be noted that
it's not a futuristic example, as this approach has already been applied to a drug
called Herceptin. A drug that would not have won FDA approval without
rationally selecting patient populations. This according to NBN background text.
And Gleevec is a well-known example of a rationally-developed targeted drug
that has made an enormous impact on patients with CML, a type of
leukemia.
Translational
or targeted drug development and
assessment using NBN resources could go as follows
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Standardized collection of biospecimens. |
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Find novel targets using microarrays. |
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Refine diagnosis and
identify high- and low-risk disease. |
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Find clinically useful biomarkers by identify correlations between gene expression profiles and treatment responders. |
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Select the appropriate patients for targeted-phase studies. |
The result is that smaller studies will be needed to achieve statistically significant results, providing relief from the competition for patients.
Fewer patients will be subjected to the toxicity of drugs that cannot help them.
The new favorable circumstances causing increased interest in trials and cancer research among patients, investigators, commercial entities ...
Obviously, it will be best if
all
organizations work cooperatively and support broad adoption
and full funding of the NBN blueprint. But it will also help if support
for the idea is expressed by the patient community.
Since, the blueprint is not cancer-specific, the rationale and need should
have broad appeal. Since
cancer affects almost everyone in the long run, it should have broad support
in the general public when they become educated about the potential and
the need.
~ Karl Schwartz
Click
here to comment on the NBN
Is it Ethical to Require a Tissue Biopsy of Participants in
Therapeutic Clinical
Trials?
Requiring a biopsy for entry into a therapeutic study is a contentious area in clinical research …
some arguing that it can sometimes be a form of coercion
… as in: sorry, no tissue, no trial.
In a treatment study, the rationale for the need to acquire
additional tissue (such as by biopsy) should be
presented clearly, because it is not a minor or risk-free
procedure. Further, the need for a biopsy should be stated up
front before the patient travels to the center.
Patients should look for eligibility criteria such as:
"Measurable disease by CT scan, defined as at least 2
lesions that measure >1.5 cm in a single dimension (one of
which is superficial and easily accessible for biopsy)."
"The
consent form should clearly indicate whether the new biopsy
is required to make the treatment decision in the trial
itself, or whether it is only done to provide information
leading to future decision making (benefiting the future,
but not the patient him/herself), a more altruistic decision
to make." (Hans, advisor to PAL)
Further, it should be made clear to the
patient that NOT giving consent for additional uses of the
tissue -- beyond the trial -- will not exclude you from
participating in the trial. (Mike)
Mike also
writes:
"The rationale
behind the requirement drives the ethics of whether a biopsy
should be taken.
Does the biopsy help to safeguard the patient’s health? It
may be necessary to examine it to confirm
the diagnosis or the grade of the disease – both of which may be
critical in accepting the patient for the
trial.
(Similarly a bone marrow biopsy is required to make sure
that you are eligible for radioimmunotherapy in regular
clinical practice.)
Does the biopsy provide a critical “before” snapshot of the
disease, prior to treatment? Trials are quite different from
normal treatment. For standard care, we don’t really care
about the mechanism of treatment so much as the results – is
the cancer gone? Has progression been halted? Did the
patient achieve a complete response? In a clinical trial,
researchers often need to know more than that – the actual
mechanism by which the experimental treatment is working."
There are many
dedicated people involved in the approval of trial protocols,
such as the Institution Review Board, the FDA and in many cases
a team of experts which will often include patient advocates
involved in the vetting of the trial protocol. So in most cases
when tissue is required it will based on sound research
principles, needs, and also attention to patient safety.
For example, tissue might be required when there's a
need to make sure that you are eligible for the trial protocol,
or for studies of targeted drugs when t can be important to
make sure that the drug that you will receive is appropriate -- that
the target exists in the tumor, in order to avoid giving you a drug that is
unlikely to be effective but sure to have side effects.
NOTE: The existence of the target in the tumor cells improves
only the plausibility that the drug can have an effect on the
tumor, but it in no way assures that you will benefit - that you
will live longer or better because of it.
Can tissue from a prior biopsy be used instead?
It depends on what kind of information is needed from the tissue
and how that tissue was captured, fixed, and stored; and perhaps
how long ago it was acquired – because the lymphoma cells can
change over time. It may also depend on the willingness of the
center that stores the tissue to release it to another center.
Finally, Mike
writes: "Considering the woefully small participation in clinical
trials overall, it is to researchers benefit to reduce the
number of barriers erected to potential participants, and to
collect only the tissue that is necessary to protect
the patient and to validate the study results."
We cannot make progress against lymphoma (the purpose of
research) without examination of the genetics and underlying
biology of the cells, which can be unique to each patient, which
needs to be correlated with clinical outcomes to help one day
personalize our care.
i
Many thanks for
the informed comments of advisors on this topic, which we've
copied directly into the text.
~ Karl (advocate's
perspectives)
Additional reading:
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Issues Surrounding Biospecimen Collection and Use in Clinical
Trials
Allison R. Baer, RN, BSN, Mary Lou Smith, JD, MBA, Deborah
Collyar, BS, and Jeffrey Peppercorn, MD, MPH
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900874/
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NEWS:
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What is caHUB?
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Request for Input on the Biospecimen Procurement Program for the
NCI's cancer Human Biobank (caHUB) http://bit.ly/9729P3
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Lymphoma clinical trials including Gene
expression analysis http://bit.ly/8Y8lGR
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The Biology of Human Lymphoid Malignancies Revealed by Gene Expression Profiling
Louis M. Staudt and Sandeep Dave http://www.pubmedcentral.nih.gov
(full text)
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Bio-bank 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."
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Ownership Issues
Based on candid feedback from a prominent
lymphoma investigator, local institution “ownership” of extra
tissue seems a major challenge to implementing the caHUB – along
with competing research interest, at least at the major centers.
So who “owns” or more precisely decides on use
of the extra tissue? The surgeon, the pathology department, the
larger institution who owns the storage units, the patient’s
treating physician, or the patient?
It seems that we are too often defaulting to No Use (discarding it),
or Unproductive Local Use, because the institutions haven’t thought
this through and believe they have ownership rights in these
matters. It seems a legal and ethical question begging for a
process to deliberate it.
Some suggestions:
·
A Stick: Perhaps participation in caHUB could
be required for any center that receives Federal monies? Consenting
standards might be required of any institutions that take and store
diagnostic tissue samples as a condition of Federal licensing, with
an option to send extra tissue to caHUB if those standards cannot be
met.
·
Carrot: Centers that participate in caHUB might
be given advertizing money to inform the public of the added benefit
of coming to their center for diagnostic procedures. (Or be named
in such ads, similar to what is done for franchise businesses)
·
Public Education: NCI should explain the vital
role of caHUB in the public media. It could be important to raise
awareness of tissue ownership issues, and how use of tissue is being
decided on today (contentiously or by default).
·
Dealing with competing interest: Perhaps an
independent advisory committee could be formed to decide on these
matters, with strong patient representation – to decide which
research projects have the most scientific promise and are the best
fit for any previously signed consent agreements. Individual
patients can opt out, always, but the recommendation of the
committee might be binding otherwise.
There seems an urgent need to cut the Gordian knot: the contentious
debates over use of tissue, by every stakeholder but the patient.
Resources
-
The NBN blueprint
document: (~226 pages)
PDF
(It may take some time for this large document to appear in your browser.)
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Molecular Targeting in the Treatment of Cancer: An Interview With
Brian Druker, MD Medscape
(free login req.) Related commentary: See the National
Biospecimen Network
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Staudt, Gene Expression
Profiling of Lymphoid Malignancies -
Annu.Rev.Med.2002.53:303–18 PubMed
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Advances in the Treatment of Non-Hodgkin's
Lymphoma - Dr. Cheson Medscape
(free login)
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Innovation or Stagnation? Challenge and Opportunity on
the Critical Path to New Medical Products PDF
2004 FDA 2004
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Molecular Diagnostics
Rita M. Braziel, Margaret A. Shipp, Andrew L. Feldman, Virginia Espina, Mary Winters, Elaine S. Jaffe, Emanuel F. Petricoin III and Lance A. Liotta
asheducationbook.org
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Primer on Medical Genomics Part III: Microarray Experiments and Data Analysis
Ayalew Tefferi, et al. Mayo Clin Proc. 2002;77:927-940 PDF
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Clinical Application of cDNA Microarrays in Oncology ~ Full
text theoncologist.alphamedpress.org/
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Gene expression profiling in Follicular Lymphoma to assess
clinical aggressiveness and to guide the choice of treatment.
Blood. 2004 Sep 2 PMID:
15345589 | Related
abstracts
[2266] Follicular Lymphoma: Design of a
Protein-Based Survival Predictor Using Tissue-Microarrays (TMA).
Session Type: Poster Session 479-II ASH
2004
[1125] Gene Expression Profiling Analysis in Splenic
Marginal Zone Lymphoma Allows To Predict Survival and Histological
Transformation. Session Type: Poster Session 279-I ASH
2004
Scientists Unlocking Lymphoma's Secrets - The
microenvironment accessatlanta
"Genetic differences -- not in lymphoma cells, but in immune
cells surrounding the tumor -- may determine how aggressive a
particular case of follicular lymphoma turns out to be"
Molecular Diagnostics on Lymphoid Malignancies ~ Wing C. Chan, MD; Kai Fu, MD, PhD
allenpress.com
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Study Demonstrates Gene Expression Microarrays Are Comparable
And Reproducible sciencedaily.com
"A study funded by the National Cancer Institute, part
of the National Institutes of Health, shows for the first time
that microarray data generated in different laboratories can
produce highly comparable results. For this comparison study,
appearing in the Jan. 15, 2005, Clinical Cancer Research*, four
separate laboratories analyzed gene expression (whether genes are
turned on or off) for the same set of human tumor tissues.
Overall, the expression profiles of portions of individual samples
were highly comparable, and the experimental correlation between
separate labs was only slightly lower than correlation of
duplicated experiments within the same labs."
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Researchers Use Novel Technology To Extract RNA From
Archive
Formalin-fixed Paraffin-embedded Tissue sciencedaily.com
"Recent advances in both laser-capture microdissection (LCM)
technology and microarray technology have revolutionized our
investigation of the genetic basis of human cancer," ...
"Pure cell populations can now be isolated ... and evaluated
for changes in gene expression that accompany the development of
cancer. However, applying these techniques to archived clinical
specimens has been limited by our inability to extract
high-quality genetic material from routinely processed clinical
samples."
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How patients can help accelerate advanced tissue-based
research http://biospecimens.cancer.gov/
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Improving Diagnosis and Treatment of Lymphomas with Gene
Expression Profiling hematology.org
Joseph M. Connors, M.D.
"Major new insights into the biology of lymphomas have
resulted from the use of microarray gene expression technology to
elucidate their underlying biology and to identify novel pathways
for therapeutic intervention."
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Biobank Central biobankcentral.org
BioBank Central aims to describe the
activities of modern biobanks in all their breadth, ranging from
the absolute requirement to protect the interests of patients and
healthy volunteers who choose to donate samples and data, to the
critical role of these biorepositories in enabling modern
biomedical research.
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caBIG: Power of Connection™ - Dr.
Barker provides a preview. cabig.cancer.gov
The video explores the challenges of cancer research and how
caBIG™
will speed research discoveries and improve patient outcomes by
connecting
the cancer community.
-
caIMAGE:
Enabling Standardization and Collaboration cabig.cancer.gov
Greater reliance on imaging in clinical care and biomedical
research, the current structure of clinical studies, and other
advances in technology have led to an enormous increase in the
quantity and complexity of cancer imaging data. Despite this
increase, however, there is little standardization of protocols
used to acquire, analyze, and annotate images among cancer centers
and other research facilities.
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GenePattern - Integrated
Genomics - now a part of caBIG cabig.cancer.gov
One feature unique to GenePattern is the ability to track the
different steps that a researcher takes when analyzing a set of data.
These computational and research steps, known as a “pipeline,” are
stored along with their parameters on the GenePattern server.
Researchers with access to the dataset can request that the same
analytical steps, or “pipeline,” be repeated and/or combined with
other pipelines. Reproducibility, an essential feature of many
successful research projects, can be easily accomplished using
GenePattern. Also, the ability to string together pipelines opens the
door to new discoveries by enabling the exploration of increasingly
complex hypotheses.
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Modernizing
Cancer Research PAL PDF
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Tissue preparation (devil in the details)
www.nature.com
According to experts, there are more than a billion tissue samples
archived in hospitals and tissue banks around the world, most of
them formalin-fixed and paraffin-embedded (FFPE). Today, these
samples present both an incredible opportunity and a huge
challenge to researchers. FFPE tissue samples have been
extensively annotated and well preserved, allowing detailed study
of the progression of diseases such as cancer. But due to the
method of preservation, obtaining biomolecules from these samples
is proving difficult, to say the least.
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Biobanking of fresh frozen tissue: RNA is stable in nonfixed
surgical specimens www.nature.com
| PDF
Our data indicate that nonfixed tissue specimens may be
transported on ice for hours without any major influence on RNA
quality and expression of the selected genes. However, further
studies are warranted to clarify the impact of transport logistics
on global gene expression.
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NEW
The Biology of Human Lymphoid Malignancies Revealed by Gene Expression Profiling
Louis M. Staudt and Sandeep Dave http://www.pubmedcentral.nih.gov
(full text)
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