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Ownership Issues | In the News
Ethics of Requiring Tissue Biopsy for Study Participants
"Biospecimens are materials from the human
body, such as tissue, blood, plasma, and urine,
that can be used for cancer diagnosis and analysis." 27
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
human specimens for translational research."
National Biospecimen Network (NBN) has evolved into the
Cooperative Group Bank (GCB). The GCB is built on the NCI
Cooperative Group System - now called the National Clinical
Trials Network (NCTN)
So the acronyms to remember are:
NCTN - the underlying cooperative group system
(Alliance, SWOG, etc) that carries out clinical research, and
GCB - the biospecimen bank, consenting, and
informatics system that allows for science-driven collaborative
Study participant-derived biospecimens stored in the GCB are
highly annotated with detailed medical, treatment, and outcome
data - allowing for correlative research .. understanding
how the underlying biology of the disease relates to the
outcomes in therapeutic trials.
For example, the information from GCB-based correlative research
can help to identify risk factors to guide patient selection in
clinical trials ... leading ultimately to more personalized care
of patients: "getting the right drug to the right patient at the
right dose," avoiding unproductive toxicity, identifying
promising treatment targets, knowing when to continue or change
treatment ... and more.
In the News:
Standardized collection, storage, and analysis of large numbers of annotated
(tissue, blood, urine)
- so that research findings are comparable and the results can be statistically
(2) Bio-Informatics software that can store the
de-identified clinical and molecular data, linked to the samples.
(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) Consenting guidelines - including
privacy protection - to inspire trust,
and ensure participation and continued public funding.
"Currently there are no standardized
collecting, processing, storing, and distributing biospecimens." 27
" Ultimately, it may well be that the optimal treatment will be determined
clinical and biological characteristics." ~ Dr. Bruce Cheson
... 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.
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.
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
"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 
||Enable scientist to more rapidly identify the
gene mutations or 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."
||Enable scientists to link clinical behavior (such
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.
~ NBN blueprint
Note that the GCB should not represent a challenge to existing systems that are
functioning at high levels. Rather the GCB 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 GCB will incorporate new ideas and innovations as they occur. It
will constantly improve and lead to innovations that will make a real
" As we move to consider these tumors by their genetic
abnormality (genotype) rather than their
appearance (phenotype), one converts the generalities of
leukemia, lymphoma, and
myeloma into hundreds of diseases
with distinct genetic causes, clinical manifestations,
drug responsiveness." 29
Briefly, the GCB is a blueprint for creating standards for how to:
Obtain and store tissue
samples suitable for consistent analysis
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
"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
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
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
The following is one example of how the
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 GCB 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
or targeted drug development and
assessment using NBN resources could go as follows
Standardized collection of biospecimens.
Find novel targets using microarrays.
Refine diagnosis and
identify high- and low-risk disease.
Find clinically useful biomarkers by identify correlations between gene expression profiles and treatment responders.
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
organizations work cooperatively and support broad adoption
and full funding of the GCB. 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
~ Karl Schwartz
Is it Ethical to Require a Tissue Biopsy of Participants in
Ethics of Requiring Tissue Biopsy for Study Participants
Issues Surrounding Biospecimen Collection and Use in Clinical
Allison R. Baer, RN, BSN, Mary Lou Smith, JD, MBA, Deborah
Collyar, BS, and Jeffrey Peppercorn, MD, MPH
Based on candid feedback from a prominent
lymphoma investigator, local institution “ownership” of extra
tissue seems a major challenge to implementing the GCB practices – 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.
* PAL content:
Giving Tissue and Blood - an advocate's perspective
"Consent" for unspecified future use?
The NBN blueprint
document: (~226 pages)
(It may take some time for this large document to appear in your browser.)
Molecular Targeting in the Treatment of Cancer: An Interview With
Brian Druker, MD Medscape
(free login req.) Related commentary: See the National
Staudt, Gene Expression
Profiling of Lymphoid Malignancies -
Advances in the Treatment of Non-Hodgkin's
Lymphoma - Dr. Cheson Medscape
Innovation or Stagnation? Challenge and Opportunity on
the Critical Path to New Medical Products PDF
2004 FDA 2004
Rita M. Braziel, Margaret A. Shipp, Andrew L. Feldman, Virginia Espina, Mary Winters, Elaine S. Jaffe, Emanuel F. Petricoin III and Lance A. Liotta
Primer on Medical Genomics Part III: Microarray Experiments and Data Analysis
Ayalew Tefferi, et al. Mayo Clin Proc. 2002;77:927-940 PDF
Clinical Application of cDNA Microarrays in Oncology ~ Full
Gene expression profiling in Follicular Lymphoma to assess
clinical aggressiveness and to guide the choice of treatment.
Blood. 2004 Sep 2 PMID:
15345589 | Related
 Follicular Lymphoma: Design of a
Protein-Based Survival Predictor Using Tissue-Microarrays (TMA).
Session Type: Poster Session 479-II ASH
 Gene Expression Profiling Analysis in Splenic
Marginal Zone Lymphoma Allows To Predict Survival and Histological
Transformation. Session Type: Poster Session 279-I ASH
Scientists Unlocking Lymphoma's Secrets - The
"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
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."
Researchers Use Novel Technology To Extract RNA From
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
How patients can help accelerate advanced tissue-based
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."
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
caBIG: Power of Connection™ - Dr.
Barker provides a preview. cabig.cancer.gov
The video explores the challenges of cancer research and how
will speed research discoveries and improve patient outcomes by
the cancer community.
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.
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
Cancer Research PAL PDF
Tissue preparation (devil in the details)
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.
Biobanking of fresh frozen tissue: RNA is stable in nonfixed
surgical specimens www.nature.com
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.
The Biology of Human Lymphoid Malignancies Revealed by Gene Expression Profiling
Louis M. Staudt and Sandeep Dave http://www.pubmedcentral.nih.gov