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Part II: Genetic Tests in Development for Clinical Use
The aim of Part II of this project was to identify genetic tests currently
in development for clinical cancer care. During this part of the project, one
challenge was how to identify genetic tests "in development" that
were pertinent to the purposes of this horizon scan. The methods section of
this report details the systematic process that we developed and applied to
the scientific and gray literature, in an attempt to identify cancer genetic
tests with more immediate clinical and commercial potential.
The final product of this part of the project is a database of genetic tests
currently in clinical development for cancer care. These tests were identified
during our search of the scientific and gray literature as well as through
other additional resources such as expert interviews and scientific conferences.
The focus of this database was to find genetic tests that are currently under
investigation for clinical utility. By the time most medical tests in development
reach testing for clinical utility, the new technology in development usually
is associated with commercial interests. As a result, the focus of our search
for genetic tests in development centered around the LexisNexis® database,
which provides access to authoritative legal, news, public record, and business
information via a set of searchable databases that contain over 36,000 sources
of print media including newspapers, magazines, and legal documents.
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Our approach to identify genetic cancer tests in this section can be divided into three separate processes:
- Searching the scientific literature.
- Searching the gray literature.
- Scientific meetings and expert interviews.
We began with a search of the scientific literature. However, as we learned from our efforts during Part I of this project, a systematic search of the scientific literature was not likely to be useful for the purposes of this horizon scan. As a result, the focus of our search for genetic tests in development centered on a systematic review of the gray literature and in particular LexisNexis, as the source of information most applicable to our horizon scan project.
Scientific literature search. A MEDLINE® search was conducted on July 12, 2005 to address the key question of identifying genetic tests in development for cancer. Briefly, we used search terms from 3 categories:
- Diagnostic test (i.e., sensitivity and specificity, mass screening, diagnosis, predictive value, ROC curve, likelihood ratio).
- Gene or genetic or genomic test.
- Top 10 cancers by mortality (lung, colon, breast, pancreas, prostate, leukemia, lymphoma, ovarian, esophagus, liver)*.
The complete search strategy used is detailed in Appendix A4. The results of this initial exploratory search of the scientific literature were presented and discussed at an interim conference call with AHRQ. Based on a sampling of the abstracts from the MEDLINE search, it was revealed that many of the studies identified as potentially of interest were preclinical exploratory reports of potential tumor biomarkers or genes/genomic arrays with possible associations with tumor diagnosis or activity. However, the chances that any of these early preclinical biomarker reports will eventually evolve into clinically validated and useful tests are slim.4 As a result, a significant majority of these reports would not be of interest or useful for the purposes of our particular horizon scan. Together with AHRQ, we decided to focus our energies toward searching gray literature sources.
Gray literature search. As discussed in Part I, in constructing our list of
gray literature sources, we started with gray literature sources identified
by the NLM's Health Technology Assessment Information Resources.
we supplemented this list of gray literature sources with additional databases
through conversations with AHRQ (LexisNexis) and internal investigations (Google
News, Early Research Detection Network, Cambridge HealthTech). By the end of
this project, we identified 39 databases of interest; however, this list is
not designed to be comprehensive. Below is a brief description of each gray
literature source explored and the search strategies that we employed for each
For the purposes of this report, we have organized the gray literature sources
that we examined into three categories:
Category I: (High utility for the horizon scan)
a. LexisNexis (www.lexisnexis.com)
LexisNexis provides access to authoritative legal, news, public record, and
business information via a set of searchable databases that contain over 36,000
sources of print media including newspapers, magazines, and legal documents.
Sources include public records, The New York Times, CNN, Bloomberg, Dun & Bradstreet,
the Associated Press, Biotech Week, and NewsRx. This tool is the global legal
and information division of Reed Elsevier.
We searched LexisNexis under the Medical News and Business News headings.
Business News contained additional subheadings of interest: Industry News,
Business and Finance, Mergers and Acquisitions, and Knight Ridder. For the
purpose of our search, we began with the key terms "cancer" AND "test" covering
a 1 year time period. We started with these terms to cast the widest net possible.
However, if more than 1000 articles are returned for a search, LexisNexis does
not provide individual title results. When this result occurred, we first altered
the timeframe of our search and then added an additional search term in order
to be more specific in our request. If >1000 articles were returned for
6 months of records, our search terms were changed to "cancer"
AND "gene" AND "test." With
either the two or three term combinations, we were able to generate a list
of titles for a 1 year time period. (A time period of 1 year was chosen in
the hope of capturing references to genetic tests that are more advanced in
the clinical development process and perhaps more likely to be commercial available
within a relatively short time. Therefore, by limiting our search to 1 year,
we hoped to find genetic tests that might be relevant to CMS within the next
1-2 years, using the most efficient method possible.)
Two reviewers screened the list generated by the LexisNexis search for relevant
titles. Complete articles were then retrieved for the titles identified as
potentially applicable for our project. Articles were read by two reviewers
and a group decision was made regarding whether to include or exclude the test
from our database. When a test was identified for inclusion, pertinent test
information was extracted from the report and entered into the database. If
additional data on a particular technology was needed, we often were able to
extract missing information from the developer's Web site.
b. Cambridge Healthtech Institute (CHI) (www.healthtech.com/)
The Cambridge Healthtech Institute has developed and released the "CHI
ToolBar." The CHI Toolbar allows users to search eight different databases
including the Biomedical NewsAnalyzer, which is a fully searchable, online
database containing all press releases from many companies in the pharmaceutical,
biotechnology, bioinformatics, diagnostics, medical device, equipment, drug
delivery, contract research, and manufacturing industries. Additionally, this
tool provides access to the Biomedical Industry Analyzer, a directory of over
4600 companies in these sectors.
We searched the CHI database with the key terms "cancer,"
"test," and "gene." These searches were
limited to the field of oncology. We screened all of the titles
that were obtained from these searches to identify reports of interest. Next,
we retrieved and reviewed the full articles identified by our title screening
and extracted pertinent information on potential genetic tests into our database.
Category II: (Low to moderate utility for the horizon scan)
c. Computer Retrieval of In formation on Scientific Projects (CRISP) (http://crisp.cit.nih.gov/)
CRISP provides a listing of federally funded research projects conducted at
universities, hospitals, and other research institutions in the biomedical
fields. This database is maintained by the Office of Extramural Research at
the National Institutes of Health and includes projects funded by the National
Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA),
Health Resources and Services Administration (HRSA), Food and Drug Administration
(FDA), Centers for Disease Control and Prevention (CDC), AHRQ, and Office of
Assistant Secretary of Health (OASH).
We searched CRISP using the combination of key terms "cancer"
AND "test" AND "gene." Two reviewers screened the titles for
potential relevance and retrieved the complete reports for a sampling of projects.
From the initial sampling of retrieved reports, it became evident that the CRISP
database was limited to projects mainly investigating preclinical exploratory
biomarkers or genomic arrays that might have an association with tumor diagnosis or
activity. In this sense, CRISP provided information similar to a MEDLINE search or
other traditional scientific literature databases. Therefore, after consulting with
AHRQ, we decided that CRISP would be less useful to our specific task of identifying
genetic tests in development.
d. Web of Knowledge (http://www.thomsonisi.com/)
ISI Web of Knowledge encompasses both multidisciplinary and specialized content
as well as external collections, covering journals (including open access titles),
books, proceedings, patents, chemical structures, evaluated Web content, grant
funding, and preprints. All content in this database, including over 8,700
journals and 22 million patents, must meet editorial requirements to be included.
We searched Web of Knowledge using the key terms "cancer"
AND "test" AND "gene" for a time
period of 1 year. We screened a sampling of the titles that were obtained
from these searches to identify reports of interest. We then retrieved the
complete reports from a sampling of articles that represented promising leads
for cancer genetic tests in development. From this sample of articles, it became
evident that the Web of Knowledge is useful for identifying research of potential
biomarkers that are mainly in the preclinical phase of development and far
from establishing clinical utility or commercial development. In this respect,
Web of Knowledge may be considered similar to MEDLINE searches and therefore,
it was decided that this resource would not be useful for our purposes and
further exploration of Web of Knowledge was discontinued.
e. Early Detection Research Network (EDRN)
EDRN is a multi-disciplinary collaborative effort organized by the National
Cancer Institute to identify and validate potential cancer biomarkers. EDRN
focuses on speeding laboratory discoveries and their subsequent translation
to clinical biomarkers. In addition, the goal of EDRN is to "provide
timely, cost-effective clinical tests for early detection of cancer and identification
of high-risk individuals."6 This network is comprised of the following main components:
- Biomarkers Developmental Laboratories, which develop and
characterize new biomarkers or refine existing biomarkers.
- Biomarkers Reference
Laboratories, which serve as a resource for clinical and laboratory validation.
- Clinical Epidemiology and Validation Centers, which conduct and support
early phases of clinical and epidemiological research on the application
- A Data Management and Coordinating Center, which provides
statistical, logistics, information support, and develops theoretical statistical
approaches to pattern analysis of multiple markers simultaneously.
- An Informatics Center led by investigators at the National Aeronautics
and Space Administration (NASA)'s Jet Propulsion Laboratory serving as the
lead for the informatics component.
Since the goals of EDRN appeared to be similar to the goal of our horizon
scan, we decided to search the most recent EDRN report (March 2005) to identify
potential genetic biomarkers and tests that could be added to our database.
In order to stay consistent with our justifications for discontinuing extensive
explorations of databases such as MEDLINE and Web of Knowledge, we only extracted
biomarkers that had proceeded beyond the preclinical exploratory stage (phase
1 of development) and were at least being studied for clinical validity and
utility (phase 2 and beyond). (Figure 1)
f. National Research Register (NRR) (www.nrr.nhs.uk/search.htm)
The National Research Register is a database of ongoing and recently completed
research projects funded by, or of interest to, the United Kingdom's National Health
Service. We searched The National Research Register using the combination of key terms
"cancer,""test," and "gene," screening
the titles to identify reports of interest. Next, we retrieved and reviewed the full
articles that held potential for tests to be included in our database. However, the
majority of potentially relevant articles, as hinted by their titles, referred
to early preclinical, exploratory studies to identify potentially useful tests. As a
result, we decided to discontinue further exploration of this resource.
g. Canadian Institute of Scientific and Technical Information (CISTI)
CISTI is a source for information in all areas of science, technology, engineering and
medicine. CISTI began over 75 years ago as the library of the National Research
Council of Canada and became the National Science Library in 1957. It contains over
50,000 different serial titles, over 600,000 books, conference proceedings and
technical reports, and 2 million technical reports from around the world.
We searched CISTI using the combination of key terms "cancer" AND
"test" AND "gene." We screened all of the titles that were
obtained from this search to identify reports of interest and pulled the full reports
of articles that might fit our inclusion criteria above. Similar to NRR, the majority
of titles screened in CISTI referred to phase 1 exploratory studies and were thus far
from either commercial development or establishing clinical utility. We decided to
discontinue further exploration of the CISTI database because of its limited utility
to our horizon scan.
h. Google (www.news.google.com)
Google News gathers stories from more than 4,500 news sources in English worldwide
and automatically arranges them to present the most relevant news first. Results
are compiled solely by computer algorithms, without human intervention, and
include articles that have only appeared within the past 30 days.
We searched Google News using the key terms "cancer" AND "test"
AND "gene." We screened all of the titles that were obtained from this search
for reports of interest, pulling the full articles of all titles of interest. Tests
extracted from these articles of interest revealed significant overlap between Google
and LexisNexis. In addition to this redundancy with LexisNexis, the Google search engine
did not allow a search beyond 30 days. As a result of these limitations, we did not
further explore Google for this horizon scan.
i. Clinical Laboratory Improvement Amendments (CLIA) (www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfClia/Search.cfm)
CLIA regulates all laboratory testing (except research) performed on humans in the U.S.
In total, CLIA covers approximately 175,000 laboratory entities. The Division
of Laboratory Services, within the Survey and Certification Group, under the
Center for Medicaid and State Operations has the responsibility for implementing
the CLIA Program. We searched CLIA using the simple search function with the key
term "cancer." We screened all of the titles that were obtained from
this search and pulled the full reports of all articles that might fit our inclusion
criteria above. Review of these articles and tests of interest revealed that these
sources focused mainly on genetic tests currently in use. Therefore, the CLIA
database was probably more applicable and useful for Part I of this project.
j. The Office of In Vitro Diagnostics Device Evaluation and Safety (OIVD) (www.fda.gov/cdrh/oivd/consumer-otcdatabase.html)
OIVD is part of the U.S. Food and Drug Administration's Center for Devices
and Radiological Health. OIVD regulates all aspects of in-home and laboratory
diagnostic tests (in vitro diagnostic devices or IVDs), helps new IVDs reach the
medical marketplace, prevents the sale of unsafe or ineffective IVDs, and
categorizes the complexity of IVDs according to the Clinical Laboratory
Improvement Amendments of 1988, thereby defining the type of regulatory oversight
applied to the product.
We searched OIVD with the key term "cancer." We screened all of the
titles that were obtained from this search and retrieved the full reports of all
articles that had titles of interest. Review of these reports quickly revealed that
all of the relevant reports in the OIVD database referred to tests already available
for clinical use, thus making OIVD a resource more applicable for Part I of this project.
k. FDA Pre-market Approval
The Medical Device Amendments of 1976 to the Federal Food, Drug, and Cosmetic
Act (the act) established three regulatory classes for medical devices. The
amendments define a Class III device as one that supports or sustains human
life or is of substantial importance in preventing impairment of human health
or presents a potential, unreasonable risk of illness or injury. All devices
placed into Class III are subject to pre-market approval requirements. Pre-market
approval by the FDA is the required process of scientific review to ensure
the safety and effectiveness of Class III devices.
We searched the Pre-market Approval Database with the key terms "cancer,"
"test," and "gene." We screened all of the titles that were
obtained from this search and retrieved the full reports of all articles of interest.
Similar to OIVD, we found that the Pre-market Approval database identified tests
already available for clinical use, thus making it a resource more applicable for
Part I of this project.
l. ClinicalTrials.gov (www.clinicaltrials.gov)
ClinicalTrials.gov provides regularly updated information about federally
and privately supported clinical research in human volunteers. ClinicalTrials.gov
gives you information about a trial's purpose, who may participate, locations,
and phone numbers for more details. We searched ClinicalTrials.gov using the
combination of key terms "cancer" AND "test" AND
"gene." We screened all of the titles that were obtained from this
search strategy and retrieved the full reports of the titles of interest.
Similar to NRR and CISTI, most reports in ClinicalTrials.gov refer to genetic
tests in preclinical phase 1 exploratory studies and could be considered too
premature for either commercial development or establishing clinical utility.
Therefore, we limited further exploration of ClinicalTrials.gov database due to
its limited utility to our particular horizon scan.
m. Online Computer Library Center (OCLC)'s FirstSearch (www.oclc.org/firstsearch/)
The OCLC FirstSearch database retrieves records from worldwide conferences,
symposia, meetings, expositions, and congresses. This database covers a number
of disciplines including the arts, humanities, social sciences, and physical
and life sciences. Within the FirstSearch database, we searched PapersFirst
from 2004 to 2005 using the key terms "cancer" AND "test"
AND "gene." We screened all of the titles that were obtained from this
search but were unable to proceed further because the database did not allow access
or retrieval of abstracts or full text reports.
n. Health Technology Assessment Database (HTA) (www.york.ac.uk/inst/crd/htahp.htm)
The Health Technology Assessment (HTA) database contains information on healthcare
technology assessments and is produced in collaboration with the International
Network of Agencies for Health Technology Assessment (INAHTA) Secretariat,
based in Sweden. The database contains records of ongoing projects being conducted
by members of INAHTA, as well as publications reporting completed technology
assessments carried out by INAHTA members and other health technology assessment
We searched this database using the key terms "cancer" AND
"test" AND "gene." We also applied the same search terms
to the Data Abstracts of Reviews of Effects and Health Assessment Technology Database.
As indicated by their titles, these technology assessments review analytical and
clinical utility data on genetic tests already in use. Therefore, the HTA database
would be more relevant for Part I of this project.
o. NY Academy of Medicine (www.nyam.org/)
The Gray Literature Report is a quarterly publication of the New York Academy
of Medicine Library, alerting readers to new gray literature publications in
public health as they are acquired. This report was first published in 1999
and acquires materials from various organizations publishing gray literature
and gives them special cataloging treatment.
We searched the Gray Literature section of the Academy using the terms
"cancer," "test," and "gene." We
screened all of the titles that were obtained from this search and retrieved
the full reports of all articles of interest. A quick review of these titles
and abstracts revealed that this database produced reports that were not specific
to genetic tests in development. The few reports that did involve genetic testing
usually contained clinical and analytical data for already established technologies.
p. GrayLIT Network (http://graylit.osti.gov/)
The GrayLIT Network is a portal for technical report information generated
through federally funded research and development projects. It was developed
by the Department of Energy's Office of Scientific and Technical Information, in collaboration with the Department of Defense/Defense Technical Information
Center (DOD/DTIC), NASA, and the Environmental Protection Agency. The GrayLIT
Network was released in early response to recommendations from a May 2000 workshop
on the concept of a "Future Information Infrastructure for the Physical
Sciences" held at the National Academy of Sciences.
We searched the GrayLIT Network with the combination of terms:
"cancer," "test," and "gene." We
screened all of the titles that were obtained from these searches and retrieved
the full reports of a sampling of articles of interest. Abstracts from the
GrayLit Network mainly referred to tests in a preclinical exploratory phase
of development, similar to several databases mentioned earlier. As a result,
we did not choose to explore this database in further detail for the purposes
of this project.
q. Health Services Research Projects in Progress (HSRProj) (www.academyhealth.org/hsrproj/search.htm)
HSRProj contains descriptions of research in progress funded by federal and
private grants and contracts for use by policy makers, managers, clinicians,
and other decisionmakers. It provides access to information about health services
research in progress before results are available in a published form.
We searched HSRProj with the terms "cancer," "test,"
and "gene." We screened all of the titles that were obtained
from this search and pulled the full reports of a sampling of articles that might
fit our inclusion criteria. The HSRProj database identifies research focused on
health services research and not on test development. As a result, we limited our
use of this resource for this horizon scan.
Category III: (Not useful for the horizon scan)
We identified several additional gray literature tools available to explore.
However, further investigation of these sources revealed that none of the resources
would be useful for our horizon scan project. Table C lists these gray literature
resources that we identified but did not use for any part of this project.
Reasons for not using some of these resources include: no search engine, subscription
services that we were unable to access, or services clearly oriented toward
literature that was not applicable to our horizon scan on genetic testing in
Opinion leaders and scientific conferences. Interviews were conducted with
different experts representing commercial laboratories, academic hospitals,
and the FDA. Academic and government leaders were identified during our scientific
and gray literature searches, including the EDRN network of principal investigators
and consultants. Opinion leaders were affiliated with the University of Chicago,
the FDA, Quest Diagnostics, and Roche Diagnostics. In addition, we attended
two scientific meetings; (1) "Pharmacogenomics in Drug Development," a
workshop jointly sponsored by the Drug Information Association, FDA, Pharmacogenetic
Working Group, PhRMA, and the Biotechnology Industry Organization, and (2)
the 2005 American Society of Clinical Oncology (ASCO) Annual Meeting.
*Top 10 cancers in estimated deaths based on data from American Cancer Society Surveillance Research, U.S. Mortality Public Use Data Tapes, 1969-2002, and National Center for Health Statistics, Centers for Disease Control and Prevention, 2004.
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