Shaping the Future of Healthcare
Rhetoric in Health Technology Forecasting
Randall Hulshizer
December 2008
Table of Contents
Introduction ................................................................................................................... 3
Origins of Healthcare Horizon Scanning and Technology Forecasting ................... 4
Healthcare Horizon Scanning .................................................................................................................................... 5
Health Technology Forecasting ................................................................................................................................. 5
Rhetoric in HSTF ........................................................................................................... 6
Persuasion in HSTF .................................................................................................................................................... 7
Brief Examples of Persuasion in HSTF Documents ..................................................................................................... 9
Invention, Arrangement, and Style in HSTF .............................................................. 13
Invention.................................................................................................................................................................. 13
Ethos ................................................................................................................................................................... 13
Logos ................................................................................................................................................................... 15
Pathos ................................................................................................................................................................. 16
Arrangement ........................................................................................................................................................... 17
Style ......................................................................................................................................................................... 17
Rhetoric in HSTF: Prediction or Creation? ............................................................... 17
Predicting the Future ............................................................................................................................................... 17
Creating the Future ................................................................................................................................................. 18
Shaping the Future of Healthcare through Rhetoric ................................................ 19
APPENDIX - Sample technology forecast profiles ................................................... 22
Therapeutic vaccines for prostate cancer................................................................................................................ 23
Combination naltrexone/bupropion for long-term treatment of obesity .............................................................. 33
Therapeutic vaccines for lung cancer .................................................................................................................... 41
Works Cited ........................................................................Error! Bookmark not defined.
Shaping the Future of Healthcare:
Rhetoric in Health Technology Forecasting
by Randall Hulshizer, MS, MA
Introduction
As humans, we are at the mercy of the elements. Biologic, climactic, geologic, and cosmic forces
shape the world in which we live, and through science we seek to understand and predict natural
events that might have an impact on our way of life—either positive or negative. For example,
the seismologist uses scientific tools and methods to study and predict the occurrence of
earthquakes. They do this so that we may adjust our behavior, our activities, accordingly, in
order to minimize negative impact (e.g., financial loss, personal injury or death) or to maximize
benefit for individuals, groups, or human society at large. Forecasters can often predict events
that occur with regularity, and have little trouble determining their subsequent impact on society.
However, some events occur without warning or occur outside of expected patterns, and
forecasters find it difficult, if not impossible, to predict their occurrence and/or their potential
impact on human society.
The natural world has been used as a metaphor to describe the current state of healthcare
technology development and emergence in the United States and globally.1 New medical
technologies (drugs, devices, procedures, therapies, etc.) emerge under the pressure of market
forces, scientific innovation, and the religious, cultural and ethical climates of human societies.2
This volatile environment can make decision-making difficult for those in the position to choose
between established health care technologies and new technologies with yet uncertain clinical
outcomes and unpredictable ethical, political, and social consequences. Therefore, as society
relies on early warning systems to predict climactic and geologic events, various players in the
healthcare arena (e.g., policy makers, clinicians, healthcare providers, insurers) rely on
information—predictive information—to avoid potential harm and to capitalize on potential
benefit to a target group or groups (e.g., the healthcare industry, economy, patients).2
The disciplines of healthcare horizon scanning (HS) and healthcare technology forecasting
(HTF) have been formulated to provide this type of information to key decision-makers within
the healthcare arena. Organizations involved in healthcare horizon scanning and technology
assessment (HSTF) maintain a position of neutrality, often claiming to be “unbiased and
objective” in their presentation.3,4 They state that they “inform decision-makers” and provide
“fact-based assessments of emerging technologies.”
Shaping the Future of Healthcare 4
The name of each discipline implies its role within the healthcare environment: HS – to scan the
horizon for upcoming “events;” HTF – to predict outcomes and/or potential impact for harm or
benefit resulting from the detected events. HSTF appears to view these “events” (e.g., emergence
and/or diffusion of a new technology) as similar to the inevitable events detected by an
earthquake early-warning system. Reports generated by an HSTF organization, therefore, present
future events as probable or certain, and that can or should be avoided or capitalized on for
benefit.
However, questions arise regarding the nature of such events. Two main views exist regarding
how HSTF may interact with future events. One view sees future events as fixed and unalterable
but that can be predicted and described, and asserts—somewhat paradoxically—that actions can
be taken to avoid or embrace consequences.5 The second view asserts that no single future exists,
but that many futures are possible depending on current actions.6 And so the question: Are these
future events (e.g., the development, emergence, and diffusion of new technology) inevitable
events that should merely be embraced or avoided, or can these future events be modified by
present action? If the former is true, then HSTF serves, as is supposed, as an early warning
system of inevitable events. If the latter is true, however, then HSTF becomes an active shaper of
the future of healthcare.
In this present work, I examine HSTF from a rhetorical perspective, demonstrating that these
disciplines play a key role, not merely in informing decision-makers of inventible future events,
but in actively shaping the future of healthcare by presenting a vision of one possible future. Due
in large part to the breadth of the current literature in HSTF, I have chosen to focus on two key
organizations—and their representative publications—within the United States, one of which
operates as a non-profit organization (ECRI Institute, Plymouth Meeting, PA, USA) and the
other which operates as a for-profit enterprise (Hayes, Inc., Lansdale, PA, USA). After a
discussion of the history and use of rhetoric in HSTF, I examine the rhetorical position of the two
organizations by juxtaposing Lloyd Bitzer’s theory of “Rhetorical Situation” with Richard Vatz’s
revision of the same theory.7,8 Finally, using Vatz’s conception of rhetoric as a framework, I
discuss the evident role of HSTF operating under this framework.
Origins of Healthcare Horizon Scanning and Technology Forecasting
Within the past 40 years, key individuals in the healthcare industry recognized the need for a
method to help decision-makers choose which technologies to implement to maximize benefit
and minimize harm. In response, they formulated a systematic, evidence-based method for
examining healthcare technologies. Their method was based on an earlier method, called
technology assessment (TA), previously developed in the early 1960’s, to analyze cost-benefit
and environmental impact of various industrial technologies. Published in 1972, Archie
Shaping the Future of Healthcare 5
Cochrane’s seminal work on healthcare effectiveness defined a new scientific approach to
examining evidence and measuring outcomes in terms of what impact each technology had or
might have in several key areas, such as patient health, cost, and healthcare process (9). Since
that time, the disciplines of evidence-based medicine (EBM), evidence-based healthcare
(EBHC), and health technology assessment (HTA) have evolved into mature, analytic methods
for deciding between the “good” and the “bad” among healthcare technologies. Although some
argue that bias exists within this systematic method for analyzing medicine and healthcare
technology, empirical evidence supports the social, economic, and health-related benefits
resulting from these disciplines.2
Healthcare Horizon Scanning
As HTA began to mature and become a permanent fixture within the healthcare environment,
those within the HTA discipline became acutely aware of a need for a system to “weed out”
extraneous and non-consequential technologies before they reached market. Because of the huge
quantity of new technologies in development at any given time, early scanning systems were
needed to detect and watch technologies with the potential to become topics for HTA. Thus, HS
was born. HS systems scan the research and development horizon, alerting HTA practitioners of
“up-and-coming” technologies that might eventually be included in an HTA report—if or when
sufficiently robust data becomes available for the technologies.2
Health Technology Forecasting
Although HTA helped decision-makers evaluate technologies, its methods relied heavily—and
still do to the present day—on robust evidence from large, well-designed, human clinical trials.
HS identified numerous “early” technologies with potentially huge positive or negative impacts
on various aspects of future healthcare. However, robust evidence is rarely available for
technologies in early-phase development, and it is often unavailable in technologies that have
progressed through several human clinical trials. HTA practitioners became aware that HTA
could not sufficiently deal with early-phase technologies or technologies just emerging on the
healthcare horizon, and another discipline was needed to fill this gap.
Using various analytic models on technologies identified through HS, forecasters began to
predict the probable or potential outcomes—or impacts—that these technologies would likely
have if or when they reached market. Health technology forecasting (HTF) appealed to many
decision-making groups including investors, public and private insurers, government agencies,
executives from hospitals and healthcare systems, physicians, and other healthcare professionals.
Rather than wait for sufficient “evidence,” these groups and individuals demanded early
“notification” of trends in healthcare research and development with an emphasis on potential
outcomes specific to their own interest. For examples, investors may be most interested in
Shaping the Future of Healthcare 6
whether a technology will be profitable, while a physician may be most interested in whether a
technology will have a positive impact on patient health and quality of life. HTF then, became
inseparably linked to HS, as the “early warning system” for HTA, informing it, not only of
potential technologies, but also of the probable outcomes resulting from the use and
dissemination of the identified technologies.2,5,6
The early-warning-system metaphor, or more properly the earthquake early warning system
analogy, has informed the HSTF discipline since its inception. Like the recipients of an
earthquake warning, many producers and most readers of HSTF documents view technology
forecast reports as informative, predictive statements that “warn” of inevitable, or at least
probable, future events. However, a critical evaluation of the role of HSTF and its functions
within healthcare reveal that HSTF not only informs, but also persuades through the use of
rhetoric; and in persuading, plays a major role in shaping the future of healthcare.
Rhetoric in HSTF
In its basic meaning, a “true” statement represents reality. For example, I may say, “There is a
maple tree growing in my front yard.” If this statement accurately reflects a situation (i.e., a
maple tree does grow in my front yard), then this statement could be considered true. That is, it
describes reality, or “truth.” If no tree grows in my yard, or if it is an oak instead of a maple, then
the statement is “false.” Because a true statement must describe reality, it is bound by verifiable
evidence. I can verify that the maple tree grows in my yard by simply walking into my yard and
identifying the tree. If I cannot verify the statement with empirical evidence, I cannot claim that
it is statement is true. For example, I may say, “The quark is the smallest particle of matter.”
While this statement might reflect reality—or it might not—I cannot verify it with empirical data,
because no instruments currently exist to detect particles smaller than the quark. Therefore, my
statement is “possible,” rather than “true” or “false” because it deals with potential or even
probable truth, but not verifiable truth.
In any case, whether a statement is true, false, or possible, it falls into one of two (or a
combination of both) categories: informative or persuasive. An informative statement merely
attempts to transmit information, while a persuasive statement advocates a particular point of
view and seeks to move the receiver from his or her own viewpoint to that of the speaker or
writer.
Aristotle defined rhetoric as “the faculty of observing in any given case the available means of
persuasion”.10 Tradition has also attributed to Aristotle the declaration that rhetoric makes use of
three main avenues of appeal: pathos (emotions), ethos (moral character of the speaker/writer),
and logos (logical argument). These three appeals find themselves the subject of the first
Shaping the Future of Healthcare 7
traditional canon of rhetoric, namely invention.11 The concept of rhetorical invention, or the
search for the most persuasive ways to present information, has caused some to question the
legitimacy of rhetoric throughout history. Indeed, Plato’s negative opinions of rhetoric and his
attacks on the Sophists for their so-called “cultural relativism” have also contributed to a largely
negative popular view of rhetoric.11
Persuasion in HSTF
Not surprisingly therefore, HSTF organizations do not readily admit to the rhetorical nature of
HSTF documents. The following is taken from the nonprofit ECRI Institute’s statement
regarding their HSTF product called Health Technology Forecast:
ECRI Institute's Health Technology Forecast is an online horizon scanning
tool for healthcare executives and clinicians in key decision-making roles who
need to stay abreast of new developments in healthcare technologies and
services. Forecast monitors research and developments in various clinical
service areas as well as across new classes of technologies. ECRI Institute’s
Forecast distinguishes itself from other health technology tracking information
by offering ECRI Institute’s unique perspectives and predictions about trends
and technologies to watch based on 35 years of experience as healthcare
technology evaluators and our Advisory Board’s input. Information on this
site is updated continually as ECRI Institute scans and researches information
about up and coming technologies.12
In this excerpt, the writer admits that the product’s goal is to predict or forecast “up and coming
technologies.” However, the writer states that the tool is for “healthcare executives and clinicians
in key decision-making roles who need to stay abreast of new developments in healthcare
technologies and services.” The words “stay abreast” imply that the document’s purpose is to
inform rather than persuade.
The for-profit company Hayes, Inc., makes a similar statement regarding its HSTF product,
Hayes Prognosis, which is part of its INSIGHT product line:
Hayes INSIGHTS delivers evidence-based information and consulting to
support the selection, acquisition, and implementation of new healthcare
technologies in the hospital setting.
Every year, manufacturers invest billions of dollars developing and marketing
new healthcare products as “must haves” for the clinical environment. This
explosion of new technology drives the increasing cost of healthcare
Shaping the Future of Healthcare 8
worldwide. Providers need a resource that objectively evaluates the clinical
evidence regarding the adoption of these new technologies. The information
provided by Hayes INSIGHTS supports decision makers facing market
pressures to acquire and implement new healthcare technologies.
Hayes INSIGHTS supports decision makers with clinical evidence and
essential information through our extensive Knowledge Center that includes:
Hayes Technology Prognosis, a horizon scanning tool for healthcare policy
developers, decision makers, and providers, who must anticipate and plan for
emerging health technologies.13
In this excerpt, the writer uses the term “evidence-based information” to imply an unbiased and
objective view of up-and-coming medical technologies. The purpose of these documents is to
“support” decision makers, not to persuade them.
Because many readers would likely take offense to overt persuasion, it is clearly not strategically
advantageous for producers of HSTF content to state that their documents will seek to persuade
the reader. Instead, they create an air of objectivity to builds the reader’s confidence in the
document—and in the organization. From the reader’s perspective, he or she is not being
persuaded, he or she is being informed. The HSTF writer simply presents the facts in the case
and the reader reaches a conclusion based on inductive reasoning from those stated facts.
Because many HSTF producers are also producers of HTA (health technology assessment)
documents, this position of neutrality is perhaps natural. The HTA (health technology
assessment) discipline operates within the realm of verifiable evidence.2 An analyst
systematically reviews the available evidence, which must adhere to specific, predetermined
criteria for it to be considered valid. All HTA statements are backed by empirical, and
statistically robust, data that can be examined and verified. Although some may argue that the
process of systematic review itself is based on unfounded or faulty assumptions, the rigorousness
and thoroughness of the process provides HTA with an air of stability, reliability, and accuracy.
Again, most purveyors of HTA information claim that its purpose is not to persuade but to
provide “objective and unbiased information.” And yet, within the HTA document, evidence has
been carefully selected and arranged, and rationales (arguments) have been set forth to present a
specific viewpoint of the selected data, or in other words, to advocate a particular point of view.
While a worthy endeavor, critical analysis of the HTA process is beyond the scope of this paper.
It will suffice to say that, because of the extensive body of data and analysis, writers and readers
of HTA documents do not perceive the documents as persuasive, but rather as informative.
Shaping the Future of Healthcare 9
However, unlike HTA, with its robust and rigorous scientific method of data analysis, HSTF
often operates outside the realm of evidence.2,5,6 Instead, HSTF relies on probable scenarios and
“educated” speculation. Because HSTF makes predictive statements about future events that
cannot be verified at the present time, HSTF documents are necessarily persuasive.
Using the earthquake early-warning system as an example may help illustrate this point. When
scientists detect particular seismic activity with sensitive equipment, they may reach the
conclusion that an earthquake is imminent, and therefore make a prediction about a future event.
The collected data may be called “evidence.” However, because the event has not yet taken
place, no verifiable link between the data and the event can be established. In addition, the
statement, “A 4.0 Richter earthquake will likely occur at 8:04AM on December 2, 2008,” may at
first appear informative, but it is in fact persuasive—as are all truth-claims, whether predictive or
not. The scientist making the announcement wishes to convince the public, or some government
agency, that an earthquake will likely occur, but it cannot be proved or supported by empirical
data (except indirectly through historical data, which is controvertible). Instead, he/she uses
arguments of probability to persuade the audience that the prediction has validity.
Brief Examples of Persuasion in HSTF Documents
That HSTF documents seek to persuade can be demonstrated using two brief examples from
actual HSTF documents. The first example comes from my own writing in which I predicted
various impacts on healthcare by therapeutic prostate cancer vaccines, if or when they should
reach the market.14 The following excerpt comprises the report’s executive summary, which
appears first to the reader. The entire report and several others that I have written on other topics
may be found in Appendix A.
Therapeutic vaccines for prostate cancer
Technology Impact Ratings
Utilization Expected: (20% to 40% of the
indicated patient population)
Therapeutic cancer vaccines (TCVs) in development for prostate cancer target
metastatic, hormone refractory prostate cancer. Within this subgroup, many
will be treated with conventional chemotherapy—a treatment with proven
efficacy for many patients—but with significant side effects. Although TCVs
appear safe, strong data supporting their efficacy have not yet emerged. Due
to high costs associated with TCVs, they are unlikely to be widely utilized
unless efficacy can be better supported.
Shaping the Future of Healthcare 10
Time to Early Adoption: (2 to 4 years)
Dendreon hopes to submit positive interim data from its follow-up phase III
trial to the U.S. Food and Drug Administration (FDA) by the end of 2008. If
efficacy can be established for Provenge, FDA may grant market approval in
2009. Due to delays in the regulatory process, early adoption of this
technology may not occur within the next two years. In addition, no strong
data exist supporting the efficacy of therapeutic cancer vaccines (TCVs).
Combined with the high costs of TCVs, this may hinder early adoption of this
technology unless efficacy can be established in larger patient populations.
Health Impact: (Small)
Although therapeutic cancer vaccines (TCVs) have shown promise in early-
phase trials, late-phase trials have yielded disappointing results regarding the
efficacy and health benefits of TCVs for prostate cancer. More and larger
studies using TCVs adjunctively with chemotherapy and compared to
chemotherapy are needed to assess their ability to impact patient health and
quality of life.
Financial Impact : (Substantial)
Treatment with Provenge, the therapeutic cancer vaccine (TCV) furthest along
in trials, is expected to cost between US$45,000 and US$60,000. Since TCVs
in late-phase trials will not likely replace existing treatments for prostate
cancer, the relatively high cost of individualized vaccine production must be
added to total treatment expense.
Process Impact: (Moderate)
Administration of therapeutic cancer vaccines (TCVs) will be comparable to
traditional infectious disease vaccination—performed by injection or infusion
in an outpatient setting with a short period of observation—and will likely be
easily incorporated into existing treatment regimens. TCV preparation,
however, may require lengthy (e.g., up to 5 hours) procedures to harvest cells
from the patient, in addition to a costly manufacturing process for
individualized vaccines.
Shaping the Future of Healthcare 11
ECRI Institute's Perspectives & Predictions
Therapeutic cancer vaccines (TCVs) in late-phase development for
prostate cancer are limited to treatment of metastatic, hormone refractory
prostate cancer (HRPC). Current data show only a modest improvement in
time to disease progression and overall survival in patients treated with
TCVs for HRPC. Other trial data suggest a possible adjuvant role for
TCVs alongside chemotherapy to increase efficacy.
The estimated cost of the TCV closest to marketing approval (Provenge) is
US$45,000 to US$60,000 per patient. In addition, because Provenge
would be an adjunct treatment, it would add to overall cost of treatment
for a given patient.
If proven effective in large, late-phase trials, TCVs could provide a safer,
targeted treatment option than chemotherapy alone for patients with
HRPC.
Regulatory approval for TCVs has been stalled due to disappointing
efficacy data in late-phase trials. Unless stronger data supporting TCV
efficacy for treating prostate cancer can be obtained in late-phase trials,
TCVs are unlikely to gain marketing approval and be widely utilized or
rapidly adopted by oncology services.
One manufacturer terminated a phase III trial of its therapeutic vaccine for
prostate cancer, after an interim analysis showed a higher number of
deaths among patients who received the vaccine compared to those who
did not receive it.14
In the above excerpt, the language is clearly persuasive. Each of the technology impact ratings
states a claim, for example: “Utilization Expected: (20% to 40% of the indicated patient
population).” In this statement, I submit a truth-claim to my reader that only 20% to 40% of the
indicated patient population will use this technology. By itself, it represents a persuasive
statement by advocating a particular point of view. Combined with the rationale that follows it, it
forms a rhetorical argument based on premises and probable truth. For example, “Due to high
costs associated with TCVs, they are unlikely to be widely utilized unless efficacy can be better
supported.” In this statement, I build support for my truth-claim about utilization; one of the
reasons the technology will not be more widely utilized is because of the high costs associated
with it. I use an enthymeme (or “rhetorical syllogism”) based on probable premises: (1) high
costs will deter insurance companies from reimbursing the technology or patients from paying
out of pocket for it; (2) if the technology is effective enough, insurance companies and/or
patients will pay for it regardless of cost. If these premises are true, based on my stated
arguments my prediction should also be true—that utilization will be limited by these factors (by
Shaping the Future of Healthcare 12
how much is another question entirely, however). On a larger scale, throughout the body of the
text, I use rhetorical argument to advocate my and the organization’s viewpoint on this
technology, aiming to bring the reader’s mind to the same viewpoint.
The second example is from a report published by the for-profit company Hayes, Inc. Analysis
of the report entitled “Rivaroxaban (possibly Xarelto®) for Prevention and Treatment of Venous
Thromboembolism (VTE)” revealed a similar, yet distinctly different, rhetorical strategy
compared to the ECRI Institute report excerpted above. The writer makes truth-claims stating
that the “evidence” indicates that the drug is safe and effective for up to 5 weeks. Here, the
argument is based again on probable assumptions shared between the writer and the reader that
clinical trial data are sufficient to make claims regarding safety and efficacy of a drug. Although
the report fails to meet the criteria of an HTA report, it frequently references “best evidence” and
clinical trial data as its foundation for all conclusions. The author concludes the following:
Rivaroxaban appears to provide a predictable anticoagulation effect that
obviates the need for frequent laboratory monitoring of levels in the blood. It
has potential to replace LMWH as agent of choice for thromboprophylaxis in
patients undergoing total hip or total knee arthroplasty. Rivaroxaban also has
promise to replace current care agents in the treatment and secondary
prevention of VTE in patients with acute DVT and/or PE. However, caution
is advised for rivaroxaban prospects given the failure of a similar drug,
ximelagatran (AstraZeneca), to gain FDA approval.15
Here, as similar to the ECRI Institute report, the writer makes truth-claims, and summarizes the
basic conclusions of the report. While these statements generally lack rhetorical argument—as
the writer or organization has chosen rather to thread them into the body of the text—some
argument in the form of enthymeme exists. For example: “However, caution is advised for
rivaroxaban prospects given the failure of a similar drug, ximelagatran (AstraZeneca), to gain
FDA approval.” This statement alludes to a case where the manufacturer stopped development of
the drug ximelagatran after patients in clinical trials experienced liver toxicity. The conclusion
(i.e., caution is advised) is based on a probable premise that the failure of a “similar” drug has
valid impact on the drug written about in this report, rivaroxaban. However, a quick perusal of
the literature for each drug will reveal that although the drugs target similar disease states, their
modes of action differ dramatically. For example, ximelagatran directly inhibits thrombin, a
coagulation protein; however, rivaroxaban has little or no direct inhibitory effect on thrombin.16
Therefore, the caution stated in the Hayes report appears to use an unfounded premise to support
its claim, and the words “similar drug” strengthens the impact of the claim by linking
rivaroxaban with the failed drug ximelagatran.
Shaping the Future of Healthcare 13
Here, in these examples from two separate HSTF sources, the writers (myself included) have
used rhetoric to propose a particular view of “reality.” A fuller context is provided by the reports
available in Appendix A of this report. It is the writer’s task, within the bounds set by the
organization, to invent, as Aristotle said, the available means of persuasion. Clearly, HSTF is a
rhetorical activity in that it advocates a point of view and seeks to persuade the reader to that
position.
Invention, Arrangement, and Style in HSTF
That HSTF is a rhetorical activity—or at least incorporates rhetorical elements—has been
established by showing that HSTF documents seek, using shared assumptions and argument, to
persuade the reader to a particular point of view. Further analysis will show that producers of
HSTF documents also employ the rhetorical elements of invention, arrangement, and style to
effectively present their specific views of reality to their readers.
Invention
According to Aristotle, the effective rhetor must invent, or discover, the best available means by
which he or she may persuade the audience.10 Aristotle further claimed that these means must
employ three basic avenues of appeal: ethos, logos, and pathos.11 Ethos relates to the moral
character or authority of the speaker or writer, logos to the logical arguments set forth, and
pathos to the invoking of the hearer’s or the reader’s emotions to bring about a desired action.
Ethos
Organizations engaged in HSTF build ethos in several ways. The most common and most direct
way is for the organization to state it qualifications outright. For example, the nonprofit ECRI
Institute uses past accomplishments, expertise, and professional alliances to build reader
confidence in its products and to lend authority to its statements:
For 40 years, ECRI Institute, a nonprofit organization, has been dedicated to
bringing the discipline of applied scientific research to discover which
medical procedures, devices, drugs, and processes are best, all to enable you
to improve patient care. As pioneers in this science, we pride ourselves in
having the unique ability to marry practical experience and uncompromising
independence with the thoroughness and objectivity of evidence-based
research. We are one of only a handful of organizations designated as both a
Collaborating Center of the World Health Organization and an Evidence-
Based Practice Center by the U.S. Agency for Healthcare Research and
Quality. Our more than 5,000 member and client list includes hospitals,
Shaping the Future of Healthcare 14
health systems, public and private payers, U.S. federal and state government
agencies, and ministries of health, voluntary sector organizations,
associations, and accrediting agencies worldwide.17
In addition, ECRI Institute highlights its “key” personnel by including short biographical
sketches including educational and professional history.
The for-profit enterprise Hayes, Inc., also uses staff biographies to impress the reader with its
expertise. However, Hayes goes a step further by including prominent statements of testimonial
from past or current clients. For example:
Douglas L. Bechard, MD
Adventist Health System - Office of Clinical Effectiveness
April 2008
Hayes’ depth and breadth of analysis is far superior to anyone else on the
market. The information is a vital component of our organization’s approach
to new technology acquisition.
Steven D. Marks, MD, MHA
Chief Medical Officer & VP Health Services, PacificSource Health Plans
April 2008
PacificSource has been subscribing to Hayes products for nearly 10 years. At
this point, we utilize virtually the whole spectrum of their offerings. The
website is very useful, and we also appreciate the search capabilities related to
new and emerging technologies. We rely heavily on the currency, authority,
and completeness of Hayes reviews and citations.18
These testimonials create a powerful sense of ethos in the mind of the reader. After all, the reader
thinks, if these important individuals are saying such good things about this company and its
products, it must be true.
Beyond the organization’s direct statements designed to build ethos, the writer of the HSTF
document also plays a key role in forming ethos in the mind of the reader. One method
commonly employed is the use of technical terminology to illustrate the writer’s and the
organization’s knowledge of the given subject. The following is an example from my own
writing on prostate cancer therapeutic vaccines:
Shaping the Future of Healthcare 15
Therapeutic cancer vaccines (TCVs) are designed to stimulate the body's
natural defenses against cancer. Although many vaccines help protect against
future infections or disease, TCVs specifically target existing cancer cells or
molecules associated with cancer development and growth. During treatment,
patients are inoculated with substances known to elicit a strong immune
response against key proteins and other molecules associated with cancer.
Some of these include tumor-specific antigens (TSAs) and/or tumor-
associated antigens (TAAs)—molecules that are present at higher levels in
tumor tissue than in normal tissue. In many vaccines, chemicals known as
adjuvants are combined with tumor antigens. Adjuvants increase the
magnitude and shorten the activation time of the immune response. Once
activated, the immune system mounts a selective attack on cancer cells that
present TSAs or TAAs, or on other molecules associated with tumor cell
division and growth. TCVs may be administered alone or in combination with
surgery, chemotherapy, or radiation therapy.14
This excerpt, taken from the technology overview, explains what therapeutic vaccines are and
how they differ from traditional vaccines. By using key clinical terms such as “inoculated,”
“tumor-specific,” and “adjuvant,” the text helps build credibility and ethos by showing the reader
that the writer is knowledgeable about the topic. This gives the reader a reason to trust the writer,
and by extension, the organization at large.
Many readers of HSTF documents rely heavily on ethos created by the organization. The readers
are often busy executives who simply want to be told “the way it is.” Even in the absence of any
other appeals, a strong ethos would likely be sufficient to convince some readers of the point of
view advocated in the document.
Logos
Although ethos goes a long way toward persuading the reader, the logical arguments and proofs
set forth in the document also play a key role. Critical readers will not just take the writer’s word
as truth. Instead, they expect evidence, along with well-reasoned conclusions. In the following
excerpt from my writing sample, I discuss the potential impact of the prostate cancer TCV on
hospital operations:
Impact on Hospital Operations – Vaccination with most prostate cancer TCVs
is a simple process involving injection or infusion, a process similar to
conventional infectious disease vaccination. An observation period (e.g., 30 to
60 minutes) normally follows initial vaccination, and provided all goes well
with no untoward reaction, subsequent vaccinations are expected to require
Shaping the Future of Healthcare 16
less observation time. Most TCVs for prostate cancer will require a series of
inoculations over several weeks to months. Some may require a "booster"
injection at a later date (e.g., 6 months). Thus, vaccination is unlikely to
significantly impact hospital operations, as medical personnel currently
treating prostate cancer patients will be able to seamlessly incorporate TCVs
into their outpatient treatment regimens.13
I first lay the foundation for my proposition by drawing an analogy between these new vaccines
and currently existing, traditional vaccines. I then describe the process to show by example that
the therapy is similar to existing vaccine therapies. I conclude that implementing this new
therapy will likely not cause a major impact to hospital operations. The argument is based on the
shared assumption that a new therapy, if similar to an existing therapy, will be easy to
implement.
Pathos
Most writers of HSTF choose to eliminate or downplay the pathetic appeal in order to maintain
an air of objectivity in the document. However, appeal to pathos may be used in some instances,
such as when discussing the human impact of disease, side effects from drugs, or adverse events
in human clinical trials. For example:
For patients with hormone refractory prostate cancer (HRPC), the prognosis is
poor due to high tumor burden and/or disseminated disease. Currently,
docetaxel, a toxic chemotherapeutic agent, is the only U.S. Food and Drug
Administration (FDA) approved treatment proven effective against HRPC.
However, it has been linked to many serious side effects due to its nonspecific
toxic effects. Therapeutic cancer vaccines (TCVs) are being developed that
may help treat metastatic, disseminated, and/or recurrent HRPC without the
need for toxic, chemotherapeutic agents. These TCVs may also be used as
adjuncts to reduce chemotherapeutic side effects.14
In this except, I appeal to the emotions of the reader by stating the poor prognosis of patients
with hormone-refractory prostate cancer. I state that, currently, the only effective drugs cause
many serious and undesirable side effects, and I imply that this causes suffering for the patient.
This appeal to pathos provides a rationalization for the development of effective, but less toxic
treatments for the disease.
Shaping the Future of Healthcare 17
Arrangement
Primarily, writers of HSTF documents arrange their paragraphs, and whole documents, in a
combination of specific-to-general and general-to-specific schemes. For example, in my forecast
on therapeutic prostate cancer vaccines, I make broad statements in the bulleted list called ECRI
Institute’s Perspectives and Predictions. Throughout the body of the document, I provide details
to support each statement. The entire document is arranged to take the reader from general
conclusions to more specific details supporting the conclusions.
Style
Writers of HSTF documents usually choose to write in a formal or semi-formal, impersonal
style. This helps project an air of professionalism and objectivity to the reader. The purpose is to
produce a document similar in style to other scientific or professional literature the reader may
be acquainted with. In this way, style helps build ethos by creating the impression in the mind of
the reader that he or she is reading a professional, scientific document, similar to the peer-
reviewed literature.
Rhetoric in HSTF: Prediction or Creation?
Although some may still argue that HSTF is not a rhetorical activity—but is, in fact, an
informative discipline—there is much evidence to the contrary. First, HSTF deals primarily with
possible, rather than certain, “truth.” This being the case, the writer must gather evidence and
design arguments to support his or her, or the organization’s, viewpoint on the matter.
Necessarily, the document becomes a persuasive tool to bring the reader to that particular
viewpoint. As demonstrated above (and further in Appendix A), HSTF authors employ various
devices such as rhetorical invention (including appeals to ethos, logos, and pathos), arrangement,
and style to present a viewpoint in the most persuasive manner. But what is the purpose of this
persuasion? Why does the author, or the organization, feel compelled to convince the reader of
this particular view of reality?
Predicting the Future
Lloyd Bitzer, in his essay The Rhetorical Situation, says that “rhetorical discourse comes into
existence as a response to a situation, in the same sense that an answer comes into existence in
response to a question, or a solution in response to a problem”.7 According to Bitzer, this
situation contains three constituents: exigence, audience, and constraints. He defines exigence, in
the rhetorical sense, as “an imperfection marked by urgency,” of which something should and
can be done.7 If something should be done, but cannot, then it may be exigence, but it is not
rhetorical exigence.
Shaping the Future of Healthcare 18
In the case of an earthquake early-warning system, exigence may be created by the detection of
seismic data indicating an impending earthquake. The scientists quickly analyze the data and
conclude that sufficient evidence exists to issue a warning to human populations living near the
suspected epicenter. In their report, for example, they state the evidence and develop arguments
from past experience; they are 95% certain that this earthquake will occur. This example fits
neatly with Bitzer’s conception of rhetorical exigence, since the collected data spurred the
resulting discourse. In addition, although the forecaster is incapable of stopping the earthquake,
the report could convince the hearers to move away from danger to a safe place.
Traditionally, the terms “horizon scanning” and “health technology forecast” have been used
synonymously with “early warning system.” Therefore, the analogy of earthquake early-warning
systems has been inculcated into the minds of those producing and reading HSTF documents.
The use of metaphor and analogy in the healthcare policy arena has been critically evaluated by
Judy Segal in her article “Public Discourse and Public Policy: Some Ways that Metaphor
Constrains Health(care).”1 In her article, Segal shows that metaphors, while convenient and
sometimes helpful, can constrain and possibly warp a particular view of reality in relation to
health policy. In this case, the analogy of the early warning system has done just that—warped
the perception of HSTF and its true function in health care.
Using this analogy, HSTF serves to “detect” activity in the healthcare research environment.
With past experience as a guide, HSTF forecasters make predictions about future events that, like
earthquakes, will likely occur within a range of probability. For example, a forecaster may
predict that a particular drug has a 90% chance of reaching market. Along with this prediction,
the forecaster may predict potential adverse health outcomes to patients. In this case, the HSTF
process appears exactly like the earthquake early warning system. The forecaster is warning
about a probable future event that should be avoided by consumers. Thus, Bitzer’s exigence
arises in the probable future event, and the resulting discourse warns the susceptible population
to avoid the event.
Creating the Future
Richard Vatz responds to Bitzer’s essay by stating that Bitzer “takes the position that meaning
resides in events” and that this “meaning” brings about what Vatz calls Bitzer’s “ethical
imperative”.8 In other words, Vatz says, Bitzer thinks that there is a truth “out there” to be
discovered, and once discovered, will result in an inevitable response (i.e., the rhetorical
discourse). But, Vatz says, “meaning is not intrinsic in events, facts, people, or situations.”
Rather than rhetoric resulting from a situation, rhetoric creates the situation. He quotes Chaim
Perelman, who says:
Shaping the Future of Healthcare 19
By the very fact of selecting certain elements and presenting them to the
audience, their importance and pertinency to the discussion are implied.
Indeed, such a choice endows these elements with a presence…. It is not
enough indeed that a thing should exist for a person to feel its presence.8
Hardly could we say that the seismologist who detects certain seismic activity and reports the
possibility of earthquake to those living in the epicenter that he or she has selected, or created,
the situation. This is because, if the earthquake occurs, it was unavoidable. Such an event cannot
be created or destroyed by discourse. It can be merely be ignored or avoided.
However, in the case of HSTF, there are no inevitable events. All events are the cause of human
agents, and are therefore subject to human interaction and/or intervention. The early warning
system analogy breaks down at this point, for it is possible, through various means, not only to
predict such future events, but to alter them, or to stop them completely. The process of HSTF
selects technologies from a pool. By presenting these technologies, and not others, rhetorical
decisions have been made to “endow them with a presence,” as Perelman says.8 Perhaps a more
fitting analogy would be that of financial forecasting. For example, if the forecaster today
predicts that stock prices will fall tomorrow, he or she may not only be predicting that future
event, but causing it to happen. In other words, financial forecasting not only foretells the future,
it creates it. In like manner, HSTF may not only predict future events in healthcare, it may create
them.
Shaping the Future of Healthcare through Rhetoric
Although many within the field of HSTF would be reticent to say that they are actively creating,
or shaping, the future of healthcare with their documents, there is mounting evidence within the
literature for this role of HSTF. In a recent article published in the journal Health Policy, Claudia
Wild states that:
The fundamental function of HSS (horizon scanning systems) is therefore to
support policy makers in controlling and rationalizing the adoption and
diffusion of new technologies in healthcare practice by providing them with
timely information on new health technologies and possible consequences for
the healthcare system.6
Although at first glance, this statement appears to suggest an informative role for HSTF, the
words “controlling and rationalizing” allude to its creative role. The authors further explain that
HSTF should also function to “push… or slow down the speed of the diffusion process.” The
function of pushing technologies, Wild says, is not the traditionally accepted function of HSTF.
Shaping the Future of Healthcare 20
It was once viewed as an early warning system to predict undesirable technologies. Wild says
that:
Pushing or supporting a technology is necessary when there are conditions
that hinder an effective diffusion, irrespective of the relative advantage of the
technology. This refers to the fact that a technology needs a compatible social
and political environment to operate effectively. According to ten Velden, one
of the main purposes of HSS is therefore to support the distinction between
technologies which need particular policies and those which do not.6
The role for HSTF proposed above is clearly a rhetorical one. Not only is it rhetorical in the
sense that Bitzer envisions—where the HSTF organization reacts to a “situation”—but it is
rhetorical in the sense that Vatz proposed. Wild suggest that HSTF can and should shape and
alter the social and political environment to pave the way for selected healthcare technologies.
This selection of technologies and the “pushing” of technologies create the rhetorical situation,
and in so doing, create and shape the future of healthcare.
References
1. Segal, Judy Z. Public Discourse and Public Policy: Some Ways that Metaphor Constrains
Health(care). Journal of Medical Humanities. Vol. 18, No. 4, 1997, pp. 217-31.
2. Goodman, Clifford S. HTA 101: Introduction to Health Technology Assessment. National
Inofrmation Center on Health Services Research and Health Care Technology of the National
Library of Medicine. 2004. Online: http://www.nlm.nih.gov/nichsr/hta101/hta101.pdf
3. Main Website. ECRI Institute. https://www.ecri.org/Pages/default.aspx. Accessed October
2008.
4. Main Website. Hayes, Inc. http://www.hayesinc.com/hayes/. Accessed October 2008.
5. Conference Board of Canada. Horizon Scanning: Gathering Research Evidence to Inform
Decision Making. Health, Healthcare and Wellness. Briefing April 2008.
6. Wild, Claudia, Thomas Langer. Emerging health technologies: Informing and supporting
health policy early. Health Policy. Vol. 87, 2008, pp. 160-171.
7. Bitzer, Lloyd F. The Rhetorical Situation. Philosophy and Rhetoric. Vol. 1, No. 1, 1968, pp.
1-14.
Shaping the Future of Healthcare 21
8. Vatz, Richard E. The Myth of the Rhetorical Situation. Philosophy and Rhetoric. Vol. 6, No.
3, 1973, pp. 154-161.
9. Cochrane, A. (1972). Effectiveness and efficiency: Random reflections on health services.
Leeds: Nuffield Provincial Hospitals Trust.
10. Aristotle. On Rhetoric. Trans. George A. Kennedy. Oxford University Press, New York,
1991.
11. Bizzell, Partricia, Bruce Herzberg. The Rhetorical Tradition. Introduction. Bedford/St.
Martin’s Press. Boston, MA, 2001.
12. Health Technology Assessment Information Service. ECRI Institute.
https://www.ecri.org/Products/Pages/htais.aspx?sub=Forecasting%20and%20Trends.
Accessed October 2008.
13. Hayes INSIGHTS. Hayes, Inc. http://www.hayesinc.com/hayes/hayes_insights/. Accessed
October 2008.
14. ECRI Institute. Therapeutic Vaccines for Prostate Cancer. Health Technology Forecast.
ECRI Institute, Plymouth Meeting, PA, Published June 2008.
15. Hayes, Inc. Rivaroxaban (possibly Xarelto) for Prevention and Treatment of Venous
Thromboembolism (VTE). Hayes Prognosis. Hayes, Inc., Lansdale, PA, Updated July 2008.
16. Single Coagulation Factor Inhibitors. Thrombosis Adviser. Bayer Schering Pharma AG.
http://www.thrombosisadviser.com/scripts/pages/en/current-treatments/anticoagulants/single-
coagulation-factor-inhibitors/index.php. Accessed November 2008.
17. Pioneering Applied Scientific Research in Healthcare. ECRI Institute.
https://www.ecri.org/About/Pages/default.aspx. Accessed November 2008.
18. Hayes: About Us. Hayes, Inc. http://www.hayesinc.com/hayes/about_us/. Accessed
November 2008.
Hulshizer 22
APPENDIX - Sample technology forecast profiles
All documents in this appendix written by:
Randall Hulshizer, MS, MA
Manager, Health Technology Forecast
Senior Clinical Writer
Health Technology Assessment Group
ECRI Institute
5200 Butler Pike
Plymouth Meeting, PA 19462
Tel: +1 610.825.6000 ext. 5357
Fax: +1 610.834.1275
Email: [email protected]
Web: www.ecri.org
ECRI Institute
The Discipline of Science. The Integrity of Independence.
An independent nonprofit that researches the best approaches to improving patient care.
Designated as both an Evidence-based Practice Center by the U.S. Agency for Healthcare
Research and Quality and a Collaborating Center of the World Health Organization.
Offices United States Europe Asia Pacific Middle East
ECRI Institute
Health Technology Forecast
© ECRI Institute. Used by permission.
Hulshizer 23
APPENDIX - Sample technology forecast profiles
Therapeutic vaccines for prostate cancer
Technology Impact Ratings
Utilization Expected: (20% to 40% of the indicated patient population)
Therapeutic cancer vaccines (TCVs) in development for prostate cancer
target metastatic, hormone refractory prostate cancer. Within this subgroup,
many will be treated with conventional chemotherapy—a treatment with
proven efficacy for many patients—but with significant side effects. Although TCVs appear safe,
strong data supporting their efficacy have not yet emerged. Due to high costs associated with
TCVs, they are unlikely to be widely utilized unless efficacy can be better supported.
Time to Early Adoption: (2 to 4 years)
Dendreon hopes to submit positive interim data from its follow-up phase III trial to the U.S.
Food and Drug Administration (FDA) by the end of 2008. If efficacy can be established for
Provenge, FDA may grant market approval in 2009. Due to delays in the regulatory process,
early adoption of this technology may not occur within the next two years. In addition, no strong
data exist supporting the efficacy of therapeutic cancer vaccines (TCVs). Combined with the
high costs of TCVs, this may hinder early adoption of this technology unless efficacy can be
established in larger patient populations.
Health Impact: (Small)
Although therapeutic cancer vaccines (TCVs) have shown promise in early-phase trials, late-
phase trials have yielded disappointing results regarding the efficacy and health benefits of TCVs
for prostate cancer. More and larger studies using TCVs adjunctively with chemotherapy and
compared to chemotherapy are needed to assess their ability to impact patient health and quality
of life.
Financial Impact : (Substantial)
Treatment with Provenge, the therapeutic cancer vaccine (TCV) furthest along in trials, is
expected to cost between US$45,000 and US$60,000. Since TCVs in late-phase trials will not
likely replace existing treatments for prostate cancer, the relatively high cost of individualized
vaccine production must be added to total treatment expense.
Process Impact: (Moderate)
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APPENDIX - Sample technology forecast profiles
Administration of therapeutic cancer vaccines (TCVs) will be comparable to traditional
infectious disease vaccination—performed by injection or infusion in an outpatient setting with a
short period of observation—and will likely be easily incorporated into existing treatment
regimens. TCV preparation, however, may require lengthy (e.g., up to 5 hours) procedures to
harvest cells from the patient, in addition to a costly manufacturing process for individualized
vaccines.
ECRI Institute's Perspectives & Predictions
Therapeutic cancer vaccines (TCVs) in late-phase development for prostate cancer are limited to
treatment of metastatic, hormone refractory prostate cancer (HRPC). Current data show only a
modest improvement in time to disease progression and overall survival in patients treated with
TCVs for HRPC. Other trial data suggest a possible adjuvant role for TCVs alongside
chemotherapy to increase efficacy.
The estimated cost of the TCV closest to marketing approval (Provenge) is US$45,000 to
US$60,000 per patient. In addition, because Provenge would be an adjunct treatment, it would
add to overall cost of treatment for a given patient.
If proven effective in large, late-phase trials, TCVs could provide a safer, targeted treatment
option than chemotherapy alone for patients with HRPC.
Regulatory approval for TCVs has been stalled due to disappointing efficacy data in late-phase
trials. Unless stronger data supporting TCV efficacy for treating prostate cancer can be obtained
in late-phase trials, TCVs are unlikely to gain marketing approval and be widely utilized or
rapidly adopted by oncology services.
One manufacturer terminated a phase III trial of its therapeutic vaccine for prostate cancer, after
an interim analysis showed a higher number of deaths among patients who received the vaccine
compared to those who did not receive it.
Overview
Current treatment options for prostate cancer include active surveillance (watchful waiting for
early disease in older men), surgical prostatectomy, radiation therapy, cryosurgery, hormone
therapy, and chemotherapy. If detected early, prostate cancer can be cured using currently
available treatments in approximately 90% of diagnosed cases. Since many prostate tumor cells
are dependent on the steroid hormone testosterone, hormone therapy is often effective in treating
patients with advanced or metastatic disease. Some prostate cancers, however, are insensitive to
testosterone, and are therefore refractory to hormone therapy. For patients with hormone
refractory prostate cancer (HRPC), the prognosis is poor due to high tumor burden and/or
disseminated disease. Currently, docetaxel, a toxic chemotherapeutic agent, is the only U.S. Food
Hulshizer 25
APPENDIX - Sample technology forecast profiles
and Drug Administration (FDA) approved treatment proven effective against HRPC. However, it
has been linked to many serious side effects due to its nonspecific toxic effects. Therapeutic
cancer vaccines (TCVs) are being developed that may help treat metastatic, disseminated, and/or
recurrent HRPC without the need for toxic, chemotherapeutic agents. These TCVs may also be
used as adjuncts to reduce chemotherapeutic side effects.
TCVs are designed to stimulate the body's natural defenses against cancer. Although most
vaccines protect against future infections or disease, TCVs specifically target existing cancer
cells or molecules associated with cancer development and growth. During treatment, patients
are inoculated with substances known to elicit a strong immune response against key proteins
and other molecules associated with cancer. Some of these include tumor-associated antigens
(TAAs), molecules that are present at higher levels in tumor tissue than in normal tissue. In many
vaccines, chemicals known as adjuvants are combined with tumor antigens. Adjuvants increase
the magnitude and shorten the activation time of the immune response. Other vaccines use cells
harvested directly from the patient to produce a heightened and/or patient-specific immune
response. Once activated, the immune system mounts a selective attack on cancer cells that
express TAAs, or on other molecules associated with tumor cell division and growth. TCVs may
be administered alone or in combination with other therapies, including surgery, radiation,
chemotherapy, and hormone therapy.
Dendreon Corporation (Seattle, WA, USA) has developed Sipuleucel-T (Provenge), a TCV for
treatment of HRPC. Provenge uses immune cells, called dendritic cells (DCs), harvested directly
from the patient. After DCs are harvested, they are incubated and cultured for approximately
seven days along with a TAA called prostatic acid phosphatase (PAP) linked to granulocyte
macrophage colony-stimulating factor (GM-CSF), a powerful immune system adjuvant. This
process "activates" the DCs, which are then reinfused into the patient where they signal other
immune cells to recognize and attack tumor cells expressing PAP. Since the DCs are taken
directly from the patient, Dendreon hopes that a heightened, more specific immune response will
occur compared to standard antigen-based vaccines. A downside to this strategy is the relatively
expensive and time-intensive process of culturing individual vaccines for each patient. Treatment
with Provenge includes three infusions within one month. The infusion process takes
approximately 30 to 60 minutes, and requires patient observation for adverse events (AEs).
Cell Genesys, Inc. (San Diego, CA, USA) has developed GVAX, a whole-cell TCV designed to
treat metastatic HRPC. Whole-cell TCVs use entire cells obtained from tumors to stimulate
immune function. Following surgery, the patient's tumor cells are dissociated from the tumor
mass and genetically reprogrammed to produce GM-CSF. The cells are then irradiated to
eliminate tumorigenicity (i.e., ability to form cancerous tumors in the body) and reinjected into
the patient. After inoculation, the patient's immune system mounts a coordinated attack by
Hulshizer 26
APPENDIX - Sample technology forecast profiles
recognizing multiple TAAs present on the surface of the cells. This further stimulates specific
immune cells in the patient's body to attack any existing "live" tumor cells also presenting the
same TAAs. Because the vaccine is made from the patient's own tumor cells, which express
numerous TAAs along with the immune adjuvant GM-CSF, it may stimulate a heightened and
more patient-specific immune response than TCVs made from a single antigen. However, in
August 2008, the company terminated one of its phase III GVAX trials for prostate cancer
(VITAL-2) after the Independent Data Monitoring Committee observed a significantly higher
number of deaths in the GVAX treatment group compared to a prednisone control group. As of
September 2008, the company had not announced whether it will continue pursuing regulatory
approval for GVAX as a treatment for prostate cancer. Cell Genesys is also conducting clinical
trials with GVAX for treatment of leukemia and pancreatic cancer.
Apthera, Inc. (Scottsdale, AZ, USA) has developed NeuVax, a TCV for the treatment of
hormone-refractory, human epidermal growth factor receptor 2 (HER2)/neu-positive prostate
cancer. In normal tissue, the HER2/neu protein plays a role in cell-cycle control and apoptotic
(i.e., programmed cell death) regulation; however, it is known to be overexpressed in many
forms of prostate cancer. NeuVax consists of a short peptide fragment, called E75, derived from
the HER2/neu TAA combined with GM-CSF. After inoculation, the patient's immune system
mounts an attack on the HER2/neu-adjuvant complex as well as tumor cells overexpressing
HER2/neu. Early trials show promising results, with most patients mounting a heightened, cell-
mediated immune response, which stimulates special cells called cytotoxic T lymphocytes to kill
tumor cells that express the HER2/neu TAA. NeuVax is also in clinical trials for treatment of
early-stage, HER2/neu-positive breast cancer.
The potential ability of TCVs to stimulate the immune system shows promise in treating prostate
cancer that has spread from the primary site, has become hormone-refractory, or has recurred
following surgery or radiation. More data are needed, however, to determine if TCVs will be
most effective alone or in combination with other treatments. Clinical data currently available
from late-phase trials indicate only modest benefits using TCVs to treat advanced and/or
metastatic prostate cancer. Other trials are underway to examine TCVs as adjuvant therapy
alongside hormone therapy or chemotherapy (e.g., docetaxel) and after surgery or radiation to
prevent disease recurrence. Data from these studies are positive, but still early. In addition,
clinical trials comparing TCVs to standard chemotherapy are needed to determine the relative
efficacy and safety of TCVs versus chemotherapy.
Regulatory Status
TCVs for treatment of prostate cancer are in early and late-phase clinical trials, but none has yet
received FDA marketing approval in the United States or other countries.
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APPENDIX - Sample technology forecast profiles
Dendreon Corporation recently completed phase III clinical trials on Provenge and filed a
biologics license application with FDA to obtain marketing approval. Although Dendreon
received an "approvable letter" from FDA in March 2007—indicating FDA's recommendation to
approve Provenge—in May 2007, FDA issued a complete response letter to Dendreon asking for
follow-up efficacy data. Representatives at Dendreon estimate that the requested follow-up
studies may take until 2010 to complete, thereby delaying marketing approval and commercial
availability of Provenge. FDA has stated that it will accept positive interim data from the study,
which could be available by late 2008, to speed the process along. On January 15, 2008,
European authorities issued a broad patent to Dendreon for Provenge, a development that may
help support Dendreon's position on the commercial viability of the TCV.
In May 2006, FDA granted fast-track status to Cell Genesys' GVAX. Fast-track status is a set of
regulations that help accelerate development and review of therapeutics that fill a gap in current
treatment for life-threatening diseases. Cell Genesys is currently studying GVAX in two separate
phase III clinical trials, one of which began in 2004 and the other in 2005. However, in August
2008, the company terminated one of its phase III GVAX trials for prostate cancer (VITAL-2)
after the IDMC observed a significantly higher number of deaths in the GVAX treatment group
compared to a prednisone control group. Cell Genesys has asked the IDMC to examine the safety
of its other phase III GVAX trial for prostate cancer, VITAL-1. As of September 2008, the
company had not announced whether it will continue pursuing regulatory approval for GVAX.
Cost Issues
The estimated treatment cost for HRPC using the Provenge TCV is between US$15,000 and
US$20,000 per infusion. Since current dosing protocols for Provenge require three infusions, the
total estimated cost ranges from US$45,000 to US$60,000. Estimated costs for treatment with
GVAX and NeuVax are not currently available. Since TCVs are unlikely to replace conventional
treatments for HRPC, these costs would be added to the expense of existing treatments.
Reimbursement Issues
At this time, no data are available about whether and how TCVs will be reimbursed. However, if
Medicare and third-party payers follow trends set for existing cancer therapies, and if TCVs are
proven efficacious, reimbursement will likely follow FDA marketing approval.
Timing of Diffusion
Given the mediocre performance by TCVs for prostate cancer in late-phase trials, TCVs are
unlikely to diffuse rapidly into clinical use unless efficacy can be strongly supported in larger,
Hulshizer 28
APPENDIX - Sample technology forecast profiles
multicenter phase III trials. In addition, high costs for TCVs, which will add to existing treatment
costs, may prohibit rapid diffusion of this technology.
Impact on Hospital Operations
Vaccination with most prostate cancer TCVs is a simple process involving injection or infusion,
a process similar to conventional infectious disease vaccination. An observation period (e.g., 30
to 60 minutes) normally follows initial vaccination, and provided all goes well with no untoward
reaction, subsequent vaccinations are expected to require less observation time. Most TCVs for
prostate cancer will require a series of inoculations over several weeks to months. Some may
require a "booster" injection at a later date (e.g., 6 months). Thus, vaccination is unlikely to
significantly impact hospital operations, as medical personnel currently treating prostate cancer
patients will be able to seamlessly incorporate TCVs into their outpatient treatment regimens.
The preparation of TCVs for administration for prostate cancer, however, may have a substantial
impact. The three TCVs mentioned in this profile each require a different procedure for
preparation. The DC-based TCV, Provenge, will require cells to be harvested from the patient by
leukapheresis, a process that filters the blood and removes the components of interest. The
process may take up to five hours, during which time patient observation is needed. The DCs are
then shipped to the vaccine manufacturer for processing. After the manufacturer prepares the
vaccine, it will be shipped back to the hospital or clinic for administration to the patient. The
whole-cell TCV, GVAX, requires the retention of patient tumor cells following surgical
prostatectomy, thereby precluding radiation as an option for these patients. This process should
be relatively simple and quick, with the cells being cryopreserved (i.e., frozen) and shipped to
the vaccine manufacturer for processing. The TCV will then be prepared and shipped back to the
hospital. Apthera's NeuVax will be manufactured remotely without the need for patient samples.
Vaccination with each of these TCVs can be performed in an outpatient setting with minimal
observation time.
Patient Safety
Data currently available indicate that patients tolerate TCVs well with minimal AEs and side
effects. TCVs have demonstrated a similar AE profile to that of conventional vaccines. Most
AEs are mild, including injection-site reactions and mild fever or muscle pain. Other rare AEs
have been reported, including rigor and muscle tremor. No serious AEs have been reported for
prostate cancer TCVs. Additional clinical data from larger, ongoing trials or from clinical
registries after the vaccines are approved for marketing and diffuse into practice, are needed to
support the existing data regarding TCV safety.
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APPENDIX - Sample technology forecast profiles
In August 2008, Cell Genesys terminated its phase III VITAL-2 GVAX trial for prostate cancer,
after an interim analysis by the IDMC showed a higher number of deaths among patients who
received GVAX. Investigators have not identified a specific cause for the imbalance in deaths,
and the IDMC has not reported any new safety issues for GVAX when administered in
combination with docetaxel, according to Cell Genesys. The company plans to analyze available
trial data to discern a potential cause of the higher death rate in the GVAX arm. Following
cancellation of VITAL-2, Cell Genesys has requested that IDMC perform a previously
unspecified futility analysis of VITAL-1, the other phase III clinical trial of GVAX for prostate
cancer. VITAL-1 completed enrollment of 626 patients in July 2007. The company expects the
results of the VITAL-1 futility analysis by October 2008.
Recent and Ongoing Studies
Provenge (Dendreon)
In response to FDA's request for more detailed, positive efficacy data, Dendreon is currently
conducting the IMPACT trial, a phase III randomized controlled trial (RCT) to evaluate the
efficacy of Provenge in the treatment of metastatic HRPC. The study is fully enrolled with 500
men 18 years of age and older with asymptomatic, metastatic HRPC. Dendreon expects to
release interim results by the end of 2008. The study is scheduled to be completed in 2010.
In March 2007, Dendreon briefed FDA on the results from its most recent phase III RCT
evaluating the efficacy and safety of Provenge for treatment of asymptomatic, metastatic HRPC.
The study enrolled 98 men who were randomly assigned to Provenge (n=65) or placebo (n=33).
The primary endpoint for the study was time to disease progression (TTP). No difference was
detected in TTP between the Provenge and placebo groups (10.9 versus 9.9 weeks; p=0.719). In
addition, median overall survival was measured at 36-month follow-up, and no difference was
detected between the Provenge and placebo groups (19.0 versus 15.7 months; p=0.331).
In July 2006, Dendreon published results from a phase III RCT, concurrent with the trial
mentioned above, which evaluated the safety and efficacy of Provenge. The study enrolled 127
men with metastatic, asymptomatic HRPC. Patients were randomly assigned to Provenge (n=82)
or placebo (n=45). Prior to treatment, all patients underwent leukapheresis to obtain DCs that
were then used to prepare individualized Provenge TCVs for use in the study. At weeks 0, 2, and
4, patients received infusions for 30 minutes with either Provenge TCV or placebo. The primary
endpoint for the study was TTP. Patients were observed for AEs and disease progression every 8
to 12 weeks for the duration of the study. Median TTP was 11.7 weeks for the Provenge group
and 10.0 weeks for the placebo group (p=0.052). Median survival at 36-month follow-up was
25.9 months for the treatment group and 21.4 months for the placebo group (p=0.01). Although
the result was statistically significant, the study was not sufficiently powered to evaluate overall
Hulshizer 30
APPENDIX - Sample technology forecast profiles
survival. T-cell stimulation, a measure of immunologic response, was also measured at 0 weeks
and 8 weeks. The Provenge group showed an eight-time higher response at eight weeks than the
placebo group (16.9 versus 1.99; p=0.001). Most AEs linked to Provenge treatment were mild,
with the most common AEs being rigor (59.8%), fever (29.3%), tremor (9.8%), and chills
(8.5%). Investigators considered rigor and fever to be linked to the infusion process rather than
the study drug. No patients withdrew from the study due to AEs.
GVAX (Cell Genesys)
In 2005, Cell Genesys began the VITAL-2 trial, to compare the efficacy of GVAX plus
chemotherapy (i.e., docetaxel) with chemotherapy alone. The study planned to enroll 600 men
with asymptomatic, metastatic HRPC. In 2004, Cell Genesys began the VITAL-1 trial to
evaluate the efficacy of GVAX treatment alone compared to chemotherapy in 600 patients with
asymptomatic, metastatic HRPC.
In a statement issued August 27, 2008, Cell Genesys announced that the IDMC for the phase III
VITAL-2 trial recommended ending the trial after it observed an imbalance in the death rate
between the two trial arms during a routine safety review. IDMC observed 114 deaths so far in
the trial, of which 67 deaths occurred in the GVAX plus docetaxel treatment arm, and 47 deaths
occurred in the docetaxel plus prednisone arm. The trial had enrolled 408 of the planned 600
patients at 115 clinical trial sites across North America and the European Union. Investigators
have not identified a specific cause for the imbalance in deaths, and IDMC has not reported any
new safety issues for GVAX when administered in combination with docetaxel, according to
Cell Genesys. The company plans to analyze available trial data to discern a potential cause of
the higher death rate in the GVAX arm. Following cancellation of VITAL-2, Cell Genesys has
requested that IDMC perform a previously unspecified futility analysis of VITAL-1, the other
phase III clinical trial of GVAX for prostate cancer. VITAL-1 completed enrollment of 626
patients in July 2007. The company expects the results of the VITAL-1 futility analysis by
October 2008.
At the 2006 Prostate Cancer Symposium of the American Society of Clinical Oncology, Cell
Genesys released data from two separate, nonconcurrent, multicenter phase II trials designed to
evaluate the safety and efficacy of GVAX. The study design was the same for both trials, which
had primary outcome measures of overall survival. A total of 114 men with HRPC who had not
previously received chemotherapy were enrolled in the trials—38 patients in study A and 76
patients in study B. Prior to treatment, survival was predicted for each patient by using the
Halabi nomogram, an algorithm used to predict survival based on several baseline clinical factors
(e.g., LDH, PSA, Gleason score, presence/absence of visceral disease, etc.). Predicted median
survival for each patient group was then calculated. All patients received GVAX treatment every
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APPENDIX - Sample technology forecast profiles
2 weeks for 24 weeks. For patients in study A, median survival was 26.2 months compared to the
predicted survival of 19.5 months (p=0.01). No controls (e.g., placebo) were used in this study.
Results for study B were not made available. GVAX was reported to be well-tolerated in all
patients, with the most common AEs being mild injection-site reactions, fever, and chills.
NeuVax (Apthera)
Apthera expects to begin a phase II/III trial beginning in early 2008 to evaluate the safety and
efficacy of NeuVax as a treatment for HER2-positive HRPC. Apthera recently completed a
phase I/II study to evaluate the safety and efficacy of NeuVax for treatment of HER2-positive
HRPC. The study enrolled 50 men who previously had undergone surgical prostatectomy and
were considered at high risk for disease recurrence. Patients were assigned to a treatment (i.e.,
NeuVax) group (n=23) or a placebo group (n= 27). Although clinical data are not available,
company sources state that patients in the NeuVax group showed increased immunologic
responses toward prostate cancer cells expressing the HER2 protein. No significant AEs were
reported in either group.< /p>
Effect on Other Technologies
Currently, TCVs for prostate cancer are limited to treatment of HRPC. Many TCVs for prostate
cancer will likely find their niche as adjunct therapy with standard chemotherapy (i.e.,
docetaxel). TCVs may be used before, during, or after other treatments to weaken cancer cell
resistance to treatment, augment cytotoxic properties of chemotherapeutic agents or radiation,
and/or eliminate cancerous cells remaining after surgery. Data suggest that TCVs may be most
useful in helping prevent disease recurrence following radiation or surgery.
Selected References
Kipp RT, McNeel DG. Immunotherapy for prostate cancer - recent progress in clinical trials.
Clin Adv Hematol Oncol 2007 Jun;5(6):465-74.
Nemunaitis J. Vaccines in cancer: GVAX, a GM-CSF gene vaccine. Expert Rev Vaccines 2005
Jun;4(3):259-74.
Patel PH, Kockler DR. Sipuleucel-T: a vaccine for metastatic, asymptomatic, androgen-
independent prostate cancer. Ann Pharmacother 2008 Jan;42(1):91-8.
Slovin SF. Emerging role of immunotherapy in the management of prostate cancer. Oncology
(Huntingt) 2007 Mar;21(3):326-33; discussion 334, 338, 346-8.
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APPENDIX - Sample technology forecast profiles
Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS,
Jones LA, Hershberg RM. Placebo-controlled phase III trial of immunologic therapy with
sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate
cancer. J Clin Oncol 2006 Jul 1;24(19):3089-94.
Sonpavde G, Spencer DM, Slawin KM. Vaccine therapy for prostate cancer. Urol Oncol 2007
Nov;25(6):451-459.
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Combination naltrexone/bupropion for long-term treatment of obesity
Technology Impact Ratings
Utilization Expected: (40% to 60% of the indicated patient population)
Although the demand for weight loss drugs is high, some obese
individuals will continue to use established weight-loss
pharmacotherapies, such as orlistat or sibutramine. Others will choose behavior modification
tools only (i.e., exercise, diet) and avoid drugs completely. If safe and effective, Contrave may
successfully share the market with other weight loss therapies, but possible long-term and acute
side effects could limit its range of use.
Time to Early Adoption: (1 to 2 years)
The manufacturer, Orexigen, is currently conducting four phase III clinical trials for Contrave.
The company expects to complete all four trials by mid-2009 and, pending positive outcomes,
file a new drug application with the U.S. Food and Drug Administration later that year.
Health Impact: (Moderate)
Contrave has demonstrated relative safety and moderate efficacy (7% total weight loss [TWL])
in phase II trials. Although 10% TWL is considered essential for positive clinical outcomes,
Contrave may provide clinical benefit if combined with behavioral counseling (diet and
exercise). The manufacturer, Orexigen, is currently examining Contrave therapy as adjunct to
diet and exercise, although the data are forthcoming.
Financial Impact : (Moderate)
Contrave comprises two currently available commercial products (bupropion and naltrexone) in
a proprietary formulation. Since Orexigen invested much less in initial research and development
than novel new drugs require, the final cost of the drug should be relatively low for a new drug.
Contrave may provide some cost savings to individuals who use Contrave as an alternative to
more expensive weight loss drugs, such as orlistat. In addition, if clinical trials can firmly
establish the drug's efficacy, Contrave may decrease treatment costs associated with obesity-
related conditions, such as diabetes.
Process Impact: (Negligible)
Contrave is a once-daily, oral medication.
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ECRI Institute's Perspectives & Predictions
Contrave, a combination of two drugs (bupropion and naltrexone) that have been on the
market for different indications for decades, directly affects dopamine and opioid
pathways in the brain and may reduce food cravings by interrupting the reward pathway
associated with binge and overeating behavior in obese individuals.
In phase II trials, Contrave demonstrated moderate efficacy (~7% total weight less) and a
relatively benign side-effect profile; however, the drug will need to demonstrate stronger
efficacy in late-phase trials if it will compete with currently available weight loss drugs.
Although the constituents of Contrave have been safely used as monotherapies for several
decades, no data supporting the safe, long-term use of combined bupropion/naltrexone
are available at this time. Longer-term studies may be needed to accurately assess long-
term impact of Contrave for treatment of obesity.
Based on the historic demand for weight loss drugs, if phase III trials can firmly establish
the safety and efficacy of Contrave as a treatment for obesity, the drug will likely diffuse
rapidly and widely into clinical practice upon U.S. Food and Drug Administration
approval regardless of reimbursement status.
Overview
Treatment options for obesity include lifestyle modification (diet and exercise), pharmaceutical
interventions, and surgery (gastric bypass, banding, etc.). Current treatment guidelines
recommend lifestyle modification for all individuals with body mass indexes (BMIs) greater than
25; consideration of drug therapy for individuals with BMIs greater than 35 or 30 with
comorbidities (e.g., diabetes, hypertension); and consideration of surgical options for individuals
with BMIs greater than 40 or 35 with comorbidities. Although data indicate that surgical options
provide the greatest weight loss potential among available therapies (up to 70% excess weight
loss [EWL]), risks of complication and/or death make pharmaceutical options an attractive
alternative for many individuals. In addition, individuals with BMIs lower than 40 do not usually
qualify for surgery, and may find weight loss drugs as the only alternative to lifestyle
modification.
Two drugs (orlistat and sibutramine) are currently approved for marketing by the U.S. Food and
Drug Administration (FDA) for long-term treatment of obesity. Orlistat, available over-the-
counter (Alli, GlaxoSmithKline) or by prescription (Xenical, Roche), reduces caloric intake by
selectively inhibiting an enzyme responsible for intestinal fat digestion. Although the drug has
shown relative safety and efficacy (5% to 10% total weight loss [TWL]), gastrointestinal side
effects (i.e., loose stools, anal leakage) and high cost (approximately $170/month) may deter
some individuals seeking a convenient and effective therapy. Sibutramine (Meridia, Abbott
Hulshizer 35
Laboratories), a central nervous system stimulant and inhibitor of the reuptake of serotonin,
norepinephrine, and dopamine (DA), may induce weight loss by increasing metabolism and
decreasing appetite by promoting satiety. However, only moderate weight loss has been
demonstrated (<5% TWL). In addition, sibutramine may cause cardiovascular and
gastrointestinal side effects.
Evidence suggests that at least 10% sustained TWL is needed to yield significant, positive
clinical outcomes in obese individuals (e.g., reduce risk of diabetes, heart disease). Current
weight loss drugs fall short of this goal, and pharmaceutical companies continue to search for
novel approaches to safe and effective weight loss therapeutics, including the use and
combination of drugs previously approved for indications other than obesity.
Orexigen Therapeutics, Inc. (San Diego, CA, USA) has developed Contrave, a fixed-dose
formula combining sustained-release forms of bupropion and naltrexone. Bupropion (brand
name Wellbutrin) received FDA marketing approval for treatment of depression in 1985, for
smoking cessation in 1997, and for seasonal affective disorder in 2006. The drug works by
blocking the re-uptake of DA in the brain, and to a lesser extent, norepinephrine, thereby
increasing feelings of well-being (including satiety) and slightly increasing metabolic rate. In
clinical trials, individuals taking bupropion showed evidence of modest weight loss (<5% TWL).
Since gaining marketing approval, physicians have prescribed bupropion for reduction of weight
gain during smoking cessation efforts, and some have prescribed the drug off-label for the
treatment of obesity. Naltrexone, an orally available opioid antagonist, received FDA marketing
approval for treatment of opioid addiction in 1984 and treatment of alcoholism in 1995. The drug
effectively blocks exogenous (e.g., morphine) and endogenous opioids from binding to their
receptors and interrupting the brain's "reward pathway," which plays an important role in drug
addiction (particularly cocaine and heroin) and behavior reinforcement (sex, eating, drinking,
etc.).
Whereas traditional weight loss drugs focus on increasing metabolic rate and feelings of satiety,
Orexigen's novel approach assumes a strong behavioral factor in the development of obesity.
Although Contrave includes a metabolic rate/satiety component (blocking DA reuptake to
increase satiety and metabolic rate), Orexigen has modeled the drug after treatments for
addiction and depression. Drugs, such as cocaine and heroin, cause a large release of DA in the
nucleus accumbens of the brain, resulting in feelings of euphoria and/or ecstasy. Continued drug
use reinforces this "reward pathway," and the user begins to crave the substance. In addition,
chronic users of heroin and cocaine display a decreased response to normal DA levels in the
brain, causing users to "need" the substance in order to maintain a normal psycho-physiologic
state. Numerous studies indicate that behaviors such as eating, drinking, and sex elicit a similar
DA release in the nucleus accumbens, thereby reinforcing such behaviors. Data also indicate that
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obese individuals show a decreased sensitivity to normal DA levels, prompting some researchers
to suggest that obesity may result from addictive behavior toward food and eating.
Neither naltrexone alone nor bupropion alone have demonstrated the ability to produce
significant weight loss, but Orexigen claims that the combination of the two drugs may be
synergistic. The company hopes that Contrave will enable obese individuals to overcome their
addiction to food by increasing feelings of general wellbeing and satiety as well as by
interrupting the reinforcement of the reward pathway linked to eating. According to Orexigen,
Contrave "reduces the perceived reward [and] negatively alters the palatability of many foods,
particularly sweets."
Regulatory Status
Both bupropion and naltrexone are currently marketed in generic as well as brand name
formulations. Orexigen is currently conducting four large phase III trials for Contrave and
expects to file a new drug application (NDA) with FDA in the second half of 2009. Neither
Contrave nor its components (bupropion and naltrexone) have yet received FDA marketing
approval for treatment of obesity.
In February 2008, Orexigen announced that a recent decision to grant a patent by the European
Patent Office (EPO) might pave the way for a European patent on Contrave. Although the EPO
did not specifically address Contrave in the document, it covered the use of naltrexone and
bupropion, Contrave's constituents, for weight loss. In January 2008, Orexigen announced that
the U.S. Patent and Trademark Office had posted a Notice of Allowance for sustained release
compositions containing naltrexone and bupropion, such as Contrave. Orexigen hopes this
development will allow them to secure a patent for the drug, providing protection for Contrave
through 2024.
Cost Issues
Contrave comprises two currently available, generic commercial products (bupropion and
naltrexone) in a proprietary formulation. Since Orexigen invested little in the initial research and
development of the products, final cost of the drug should be relatively low. Based on current
costs of bupropion and naltrexone, the combination contained in Contrave would cost
approximately $83.00 per month. However, final costs to consumer will be higher as Orexigen
adds profit margin and expense of clinical trials onto manufacturing costs. If phase III trials
establish the efficacy of Contrave, the drug may provide considerable cost savings to individuals
who use Contrave as an alternative to more expensive weight loss drugs, such as orlistat.
Reimbursement Issues
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In the United States, the Medicare Part D drug benefit currently prohibits coverage for weight-
loss drugs, although the U.S. Centers for Medicare & Medicaid Services (CMS) may permit
coverage for some smoking cessation treatments that may include weight-loss drug therapy.
Changes in CMS policy language in July 2004 left room for consideration of obesity as a
disease; however, no changes in reimbursement policy have occurred since that time. CMS
currently reimburses treatments for obesity only if the condition is linked to another disease,
such as diabetes. Therefore, CMS and third-party payers will likely not reimburse Contrave for
treatment of obesity unless it is part of a treatment regimen for diabetes or other obesity-
associated comorbidity.
Timing of Diffusion
Based on the historic demand for weight loss drugs, if phase III trials can firmly establish the
safety and efficacy of Contrave as a treatment for obesity, the drug will likely diffuse rapidly into
clinical practice upon FDA approval regardless of reimbursement status. In addition, if Orexigen
employs direct-to-consumer advertising for Contrave, consumer demand for the drug will further
drive the rate of diffusion, and rapid, widespread use can be expected.
Impact on Hospital Operations
Because primary care physicians will usually prescribe Contrave in an office setting,
introduction of this drug into the obesity treatment armamentarium will not directly affect
hospital operations.
Patient Safety
The most commonly reported adverse event related to Contrave is nausea (40% of recipients),
followed by headache, dizziness, and insomnia. For several decades, bupropion and naltrexone
have been used safely for treatment of various conditions including depression and opioid
addiction, respectively. However, the long-term, combined use of naltrexone and bupropion has
not been extensively studied. Data from larger, longer-term trials are needed to accurately assess
the safety of Contrave for use as a weight loss tool.
Recent and Ongoing Studies
Orexigen has completed phase II clinical trials for Contrave and is currently conducting four
large, multicenter, phase III randomized controlled trials (RCTs) with a combined enrollment of
more than 6,000 individuals. The company expects to complete all phase III trials by mid 2009
and, pending positive outcomes, file an NDA with FDA later that year.
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Ongoing Phase III Trials
In April 2008, Orexigen completed enrollment for its NB-301 phase III clinical trial for
Contrave. Orexigen enrolled 1,742 generally healthy, nondiabetic, obese individuals into this
double-blind RCT to test the safety and comparative efficacy of two different doses of Contrave
for weight loss. Participants were randomly assigned to one of two Contrave treatment groups
(naltrexone SR 16 mg/bupropion SR 360 mg [N16 group] or naltrexone SR 32 mg/bupropion SR
360 mg [N32 group]) or a control (placebo) group. Participants in the N16, N32, and placebo
groups will receive one oral dose of Contrave (with 16 mg naltrexone SR or 32 mg naltrexone
SR) or placebo, respectively, each day for 56 weeks. Primary outcome measures include average
percentage of TWL among participants and percentage of participants achieving greater than 5%
TWL. Secondary outcome measures include proportion of participants achieving > or = 10%
TWL and waist circumference. To further examine safety and efficacy, investigators plan to
measure levels of fasting triglycerides, insulin, blood glucose, and blood pressure in all study
participants. No data are yet available from this trial. Orexigen projects trial completion by mid-
2009.
In December 2007, Orexigen initiated its NB-303 phase III clinical trial for Contrave. The 56-
week NB-303 study will enroll approximately 1,500 generally healthy, nondiabetic, obese
individuals to test the safety, efficacy, and tolerability of Contrave for weight loss. Participants
will be randomly assigned to either a treatment (Contrave) group or control (placebo) group and
will receive either oral Contrave (naltrexone SR 32mg/bupropion SR 360 mg) or placebo once
daily for 56 weeks. Outcome measures for the study are identical to those listed for the NB-301
trial above. Orexigen continues to enroll participants for the study and projects trial completion
by mid-2009. No data are yet available from this study.
In November 2007, Orexigen completed enrollment for its NB-302 phase III clinical trial for
Contrave. Orexigen enrolled 790 generally healthy, nondiabetic, obese individuals to compare
daily Contrave plus behavior modification (BMod) against BMod alone. Participants were
randomly assigned to a treatment (Contrave + BMod) group or a control (BMod only) group. All
study participants will receive intensive "group lifestyle modification counseling" (diet and
exercise counseling) for 56 weeks, and participants in the treatment group will receive one oral
dose of Contrave (naltrexone SR 32 mg/bupropion SR 360 mg) daily for 56 weeks. The primary
outcome measure for the study is change in percentage of TWL; secondary measures include
obesity-related cardiovascular risks, such as serum triglycerides, cholesterol, waist
circumference, and glucose and insulin levels. Investigators also plan to calculate the proportion
of participants achieving between 5% and 10% TWL at 56 weeks. No data are yet available, but
Orexigen expects to complete the study by early 2009.
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In May 2007, Orexigen began enrollment for its NB-304 phase III RCT for Contrave. The
company plans to enroll 525 participants with type 2 diabetes mellitus (T2DM) and BMI
between 27 and 45. The NB-304 study is designed to determine the relative safety and efficacy
of daily, oral Contrave (naltrexone SR 32 mg/bupropion SR 360 mg) versus placebo in
individuals with T2DM. Primary outcome measures include "change in baseline" of TWL and
the percentage of participants achieving greater than or equal to 5% TWL at 56 weeks.
Secondary measures include the proportion of participants achieving at least 10% TWL and less
than 7% glycosylated hemoglobin (HbA1c) value. Investigators will also measure changes in
HbA1c as a marker for effectiveness for treating T2DM. Orexigen expects to complete the trial
by mid 2009.
Completed Phase II Trial
In October 2007, at the North American Association for the Study of Obesity Annual Scientific
Meeting in New Orleans, LA, USA, Orexigen presented results from a 24-week, double-blind,
phase IIb RCT comparing the relative safety and efficacy of combined naltrexone/bupropion
(NB16, NB32, NB48) versus either naltrexone (N) or bupropion (B) alone, or placebo (P) for
weight loss. Orexigen enrolled 419 generally healthy, nondiabetic, obese individuals into the
study and randomized the participants to one of the following groups: NB16, naltrexone IR
(immediate release) 16 mg and bupropion SR 400 mg; NB32, naltrexone IR 32 mg and
bupropion SR 400 mg; NB48, naltrexone IR 48 mg and bupropion SR 400 mg; N, naltrexone IR
48 mg; B, bupropion SR 400 mg; and P, placebo. Participants received one oral dose daily for 24
weeks and continued to receive one oral dose daily for another 24-week trial extension (total 48
weeks). The primary outcome measure for the study was mean percentage of TWL. Orexigen
reported that participants in the NB 32 group demonstrated 1.5- to 2-fold greater TWL (7.1%) at
24 weeks compared to individuals in the N (1.7%), B (3.1%), and placebo (1.1%) groups (p <
0.001). In addition, results indicated that individuals in the NB groups continued to lose weight
between 24 and 48 weeks. No serious adverse events (AEs) were reported during the study. The
most commonly reported AE was nausea, which was correlated strongly with increasing
naltrexone dosage. Other reported AEs included insomnia, dizziness, and headache. The
investigators concluded that study results warranted further clinical testing, resulting in the four,
large, phase III trials mentioned previously in this profile.
Effect on Other Technologies
If phase III trials can firmly establish the safety and efficacy of Contrave for treatment of
obesity, it will likely compete with existing weight-loss pharmacotherapies (e.g., orlistat,
sibutramine) for market share. Contrave is unlikely to compete directly with surgical weight loss
interventions, such as gastric bypass surgery or banding.
Hulshizer 40
Selected References
Aronne LJ, Thornton-Jones ZD. New targets for obesity pharmacotherapy. Clin Pharmacol Ther
2007 May;81(5):748-52.
Bray GA, Greenway FL. Pharmacological treatment of the overweight patient. Pharmacol Rev
2007;59(2):151-84.
Cooke D, Bloom S. The obesity pipeline: current strategies in the development of anti-obesity
drugs. Nat Rev Drug Discov 2006 Nov;5(11):919-31.
Drolet B, Simard C, Poirier P. Impact of weight-loss medications on the cardiovascular system:
focus on current and future anti-obesity drugs. Am J Cardiovasc Drugs 2007;7(4):273-88.
Halford JC, Harrold JA, Boyland EJ, Lawton CL, Blundell JE. Serotonergic drugs: effects on
appetite expression and use for the treatment of obesity. Drugs 2007;67(1):27-55.
Huizinga MM. Weight-loss pharmacotherapy: A brief review. Clin Diabet 2007 Oct;25(4):135-
40.
Rucker D, Padwal R, Li SK, Curioni C, Lau DC. Long term pharmacotherapy for obesity and
overweight: updated meta-analysis. BMJ 2007;335(7629):1.
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Therapeutic vaccines for lung cancer
Technology Impact Ratings
Utilization Expected: (60% to 80% of the indicated patient population)
If therapeutic cancer vaccines (TCVs) prove to be effective and well-
tolerated in most patients, they are likely to become a component of
adjuvant therapy for a wide variety of cancers, including all stages of
non-small cell lung cancer (NSCLC) with or without surgery, radiation, or chemotherapy.
However, TCVs may prove useful only in selected patient groups.
Time to Early Adoption: (2 to 4 years)
Four therapeutic cancer vaccines (TCVs) for lung cancer are currently in late-phase clinical
trials, and companies developing them expect to submit data with marketing applications to the
U.S. Food and Drug Administration (FDA). Barring any unforeseen roadblocks, time to early
adoption of this technology can be expected within the next two to four years.
Health Impact: (Moderate)
Therapeutic cancer vaccines (TCVs), as adjuvant therapy, have the potential to reduce the
dosage, frequency, and duration of conventional treatments such as chemotherapy and radiation,
possibly leading to a significant decrease in toxic side effects. TCVs may also increase the ability
of conventional therapies to reduce tumor size and growth or eliminate residual cancer cells
following surgery. Early clinical data indicate a modest quality of life and survival time benefit
for TCVs in the treatment of non-small cell lung cancer (NSCLC), but larger studies are needed
to determine if this benefit will be seen in wider patient groups.
Financial Impact : (Moderate)
Therapeutic cancer vaccines (TCVs) may reduce the need for expensive, conventional
chemotherapeutic and radiation cancer therapies. The combination of TCVs with conventional
therapies may reduce treatment dosage, frequency, duration, and time to remission, thus reducing
overall costs associated with current cancer therapy. Since most TCVs in development for lung
cancer are recombinant or antigen-adjuvant vaccines, treatment is expected to be less costly than
other strategies, including autologous tumor antigen, whole-cell, and dendritic cell vaccines.
Process Impact: (Small)
Hulshizer 42
While some therapeutic cancer vaccines (TCVs) may be used as monotherapy, most will be
delivered in outpatient settings as adjuncts to surgery, radiation, and chemotherapy therapies and
will be easily incorporated into existing treatment regimens, resulting in minimal impact to
healthcare operations.
ECRI Institute's Perspectives & Predictions
If proven effective, therapeutic cancer vaccines (TCVs) may alter current lung cancer treatment
paradigms by reducing the need for conventional treatments, including chemotherapy, radiation,
and surgery.
Since many TCVs specifically target tumor cells, they may provide a better side-effect profile
than existing, nonspecific cancer treatments.
Upcoming advances in vaccine technology (e.g., whole-cell, autologous, antigen-presenting cell-
based) may prove more effective than standard antigen/adjuvant vaccine therapies currently in
late-phase clinical trials.
Several TCVs for treatment of lung cancer are currently in late-phase clinical trials and are
expected to be commercially available in two to four years. Following market approval by the
U.S. Food and Drug Administration (FDA), diffusion is expected to be rapid in the patient subsets
for which they are indicated.
Introduction of TCVs into the cancer treatment armamentarium will not significantly affect
healthcare operations or delivery of care.
Overview
More than half of cases of lung cancer are diagnosed at an advanced stage (i.e., III, IV) when
surgical resection, the first-line treatment for earlier stages, is not effective. Chemotherapy and
radiation may provide palliative relief for patients suffering from late-stage lung cancer, though
the prognosis is poor and success is limited. Therefore, interest is high in developing targeted
biologic lung cancer therapies that can be used alone or in combination with existing treatments,
to treat advanced stages of lung cancer.
Therapeutic cancer vaccines (TCVs) are designed to stimulate the body's natural defenses against
cancer. Although many vaccines help protect against future infections or disease, TCVs
specifically target existing cancer cells or molecules associated with cancer development and
growth. During treatment, patients are inoculated with substances known to elicit a strong
immune response against key proteins and other molecules associated with cancer. Some of these
include tumor-specific antigens (TSAs) and/or tumor-associated antigens (TAAs)—molecules
that are present at higher levels in tumor tissue than in normal tissue. In many vaccines,
chemicals known as adjuvants are combined with tumor antigens. Adjuvants increase the
magnitude and shorten the activation time of the immune response. Once activated, the immune
system mounts a selective attack on cancer cells that present TSAs or TAAs, or on other
Hulshizer 43
molecules associated with tumor cell division and growth. TCVs may be administered alone or
in combination with surgery, chemotherapy, or radiation therapy.
Currently, four companies are conducting or will shortly begin conducting phase III clinical trials
on vaccines for treatment of lung cancer. Because lung cancer is the most common cancer and
non-small cell lung cancer (NSCLC) comprises over 80% of all lung cancer cases, the companies
engaged in TCV development for lung cancer have focused on NSCLC.
Merck KGaA (Darmstadt, Germany) recently purchased worldwide marketing rights for
Stimuvax from the Canadian company Biomira (now called Oncothyreon, Edmonton, Alberta,
Canada). The vaccine is currently in phase III clinical trials for treatment of NSCLC. Stimuvax
consists of a synthetic form of MUC1, a TAA found abnormally glycated (i.e., sugar attached to
protein) on NSCLC tissue, as well as an immune adjuvant called monophosphoryl lipid A. These
components are packaged in a liposomal vesicle and delivered subcutaneously to four locations
on the patient's body. The liposomal delivery system allows lung tissue to easily take up the
vaccine through the cellular membrane, which may lead to more efficient delivery of the vaccine.
GlaxoSmithKline (GSK, Middlesex, United Kingdom) is developing MAGE-A3, a TCV
intended as adjuvant therapy for the treatment of NSCLC. MAGE-A3 is a protein TSA found in
several types of cancers, including NSCLC, head and neck, and bladder. GSK reports that
approximately 35% of NSCLC tumors express the MAGE-A3 antigen. The vaccine is a
recombinant (i.e., genetically engineered) form of MAGE-A3 combined with GSK's proprietary
immune adjuvant system, which is designed to increase the effectiveness of the vaccine. As an
adjuvant therapy, the MAGE-A3 vaccine is intended to be used along with chemotherapy,
radiation therapy, and/or surgery. GSK proposes that the vaccine will increase the efficacy of
existing treatments for NSCLC.
Like Merck's Stimuvax, Transgene's (Strasbourg, France) TG4010 vaccine also targets the
MUC1 protein TAA. It differs, however, in its mode of delivery and antigen presentation.
Transgene has chosen to use an off-the-shelf product derived from a genetically engineered virus
(i.e., modified vaccinia ankara [MVA]) that produces the MUC1 TAA along with an immune
adjuvant called human interleukin-2 (IL2). The virus' capability to replicate has been disabled,
thus allowing safe administration of the vaccine. The developers hope that the MVA-MUC1-IL2
combination will elicit a stronger immune response than MUC1 antigen alone and stimulate a
targeted attack against MUC1-expressing tumor cells. TG4010 is intended as adjuvant therapy
along with chemotherapy and/or radiation, often following surgery.
Bioven (Kuala Lumpur, Malaysia) has developed a TCV that targets epidermal growth factor
(EGF), an endogenous chemical messenger that plays an important role in tumor cell division
and growth. The vaccine combines a recombinant form of human EGF with the P64 protein, an
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important regulator of EGF production. The EGF/P64 complex is then adsorbed onto an immune
system adjuvant called Montanide. Upon inoculation with the vaccine, the patient's immune
system mounts an autoimmune reaction against EGF and P64 in the patient's blood. As EGF is
inactivated and cleared from the bloodstream, less EGF binds to its receptor on tumor cells, thus
inhibiting further tumor cell division and growth. Some safety concerns may exist regarding
immune stimulation against endogenous proteins, such as EGF.
Clinical trial designs and available data indicate that most TCVs will be used as adjuvant, rather
than stand-alone, treatments for lung cancer. TCVs may augment existing therapies and reduce
undesirable side effects caused by toxic radiation and chemotherapy. In addition, TCVs may
prove useful in eliminating residual cancer cells after surgery. Further developments in TCVs for
lung cancer are also expected, including whole-cell and dendritic cell vaccines that use the
patient's own tumor antigens and/or antigen-presenting cells to stimulate a stronger and more
patient-specific immune response against tumor cells than antigen-adjuvant vaccines. Several
TCVs utilizing novel strategies are in preclinical or early-phase clinical trials for treatment of
various forms and stages of lung cancer.
Regulatory Status
While four TCVs are in late-phase clinical trials for treatment of lung cancer, as of December
2007, none have received FDA marketing approval in the United States or other countries.
Within the next year, several manufacturers expect to submit new biologics license applications
—pending successful phase III clinical trial outcomes.
Reimbursement Issues
At this time, no reimbursement data are available about whether and how this will be
reimbursed. However, if Medicare and third-party payers follow trends set for existing cancer
therapies and the TCVs are proven efficacious, reimbursement will likely follow FDA marketing
approval for TCVs.
Timing of Diffusion
If efficacy of TCVs can be firmly established and U.S. Food and Drug Administration (FDA)
market approval can be achieved, this technology will likely diffuse rapidly as physicians add
TCVs to standard cancer treatment regimens.
Impact on Hospital Operations
Vaccination with lung cancer TCVs is a simple process involving injection or infusion, a process
similar to conventional, infectious disease vaccination. An observation period (e.g. 30 to 60
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minutes) normally follows initial vaccination, and provided all goes well with no untoward
reaction, subsequent vaccinations are expected to require less observation time. Most TCVs for
lung cancer will require a series of inoculations over several weeks to months. A TCV is unlikely
to significantly impact hospital operations, as medical personnel currently treating lung cancer
patients may seamlessly incorporate TCVs into their outpatient treatment regimens.
Patient Safety
Data currently available indicate that patients tolerate TCVs well with minimal adverse events
(AEs) and side effects. TCVs have demonstrated a similar AE profile to that of conventional
vaccines. Most AEs are mild, including injection-site reactions and mild fever or muscle pain.
More serious AEs are rare, but may include systemic or respiratory inflammation. Additional
clinical data from larger, ongoing trials or from clinical registries after the vaccines are approved
for marketing and diffuse into practice, are needed to support the existing data regarding TCV
safety.
Recent and Ongoing Studies
Stimuvax (Merck KGaA/Biomira- Oncothyreon)
In December 2006, Merck KGaA began the START (Stimulating Targeted Antigenic Responses
to NSCLC) trial—a phase III, multi-center, double-blind, randomized controlled trial (RCT) on
Stimuvax (L-BLP25) for treatment of patients with unresectable, stage III NSCLC. Merck plans
to enroll at least 1,300 patients and estimates a completion date of December 2010. Patients
included in this study must be undergoing concomitant chemo-radiation therapy, and must not
have undergone previous surgical and/or cancer treatments under study in clinical trials. The
primary outcome measure is survival duration, and secondary outcome measurements include
time to symptom progression, time to disease progression, and safety. As of December 2007, no
results from this study have yet become available.
On September 4, 2007, at the International Association for the Study of Lung Cancer's annual
meeting, Merck announced updated results from its phase IIb RCT showing that at 3-year
follow-up, 49% of vaccinated patients were still alive compared to 27% of patients receiving
"best supportive care" (BSC control group). Detailed trial results were previously published in
May 2005. One hundred seventy-one patients were enrolled and randomly assigned to the L-
BLP25 treatment group (n=88) or control group (n=83). Patients in the L-BLP25 group received
a single injection of cyclophosphamide followed by at least five L-BLP25 vaccinations and BSC.
Patients in the control group received BSC only. Of the entire patient group, 96.6% completed
the initial phase of treatment and 69.3% continued on to the maintenance phase. In safety
analyses, 98.9% of the L-BLP25 group and 95.2% of the control group reported AEs; however,
investigators noted that almost all reported AEs were linked to patients' disease states rather than
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the study drug. Only one serious AE, pneumonia, was considered as possibly linked to L-BLP25
treatment. The most commonly reported AEs included mild, flu-like symptoms; nausea (28.4%);
and injection-site reactions (51.1%). To determine efficacy, investigators analyzed survival,
quality of life (QOL), and T-cell proliferation (i.e., immune response). No statistically significant
differences were seen between groups in any of these measures, although reported outcomes
were improved for patients in the L-BLP25 group compared to the control group. For example,
L-BLP25 patients survived an average of 4.4 months longer than patients in the control group (p
= 0.066). Patients with stage IIIb locoregional NSCLC had a 2-year survival rate of 60% for the
L-BLP25 group and 36.7% for the control group (p = 0.069). In 166 of the 171 patients, QOL
assessments (FACT-L and TOI) were performed, and results indicated that more patients in the
L-BLP25 group maintained or improved QOL than in the control group. T-cell proliferation
analyses were conducted on 78 of the 88 patients in the L-BLP25 group. Only 21% of these
patients had a positive T-cell proliferation response. No T-cell proliferation analyses were
performed in the control group.
MAGE-A3 (GSK)
In June 2007, GSK launched a phase III clinical lung cancer trial for its MAGE-A3 vaccine.
GSK intends to recruit more than 2,200 patients worldwide with MAGE-A3 positive, completely
resected stage IB, II, or IIIA NSCLC for inclusion in the MAGRIT (MAGE-A3 as Adjuvant
Non-Small Cell Lung Cancer Immunotherapy) trial. The vaccine will be used as adjuvant
therapy. The primary outcome measure is disease-free survival. Secondary outcome measures
include overall survival, lung cancer-specific survival, disease-free survival, and safety. Prior to
enrollment, patients must have had their tumors surgically resected and with the tumor specimen
testing positive for MAGE-A3. Study participants will receive a course of 13 injections over a
27-month period.
At the 2007 American Society of Clinical Oncology's (ASCO) annual meeting, GSK announced
final results from a phase II, multi-center, double-blind RCT to determine the efficacy of the
MAGE-A3 vaccine as adjuvant therapy in stage IB and II NSCLC. One hundred eighty-two
patients were enrolled-122 in the MAGE-A3 group and 60 in the control (i.e., placebo) group.
The primary outcome measure was disease-free interval (i.e., time from surgery to relapse). At
mean follow-up of 28 months, relapse rates were 30.6% in the MAGE-A3 group and 43.3% in
the control group. GSK reported a 27% reduction in the relative risk of NSCLC relapse in
patients treated with the vaccine compared to those in the control group. However, this result
was not statistically significant (p = 0.107). Secondary outcome measures included safety and
disease-free and overall survival, but no statistically significant difference was found in disease-
free survival or overall survival between the MAGE-A3 group and the control group. Most AEs
reported were mild and occurred within 24 hours of treatment, including pain, redness and
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swelling around the injection site, or mild fever, fatigue, or muscle pain. Approximately 10% of
MAGE-A3 treatments were accompanied by more serious AEs, and 1 patient was removed from
the trial due to exacerbation of chronic obstructive pulmonary disease. Overall, however, the
vaccine appears to be well-tolerated in most patients.
TG4010 (Transgene)
Transgene is currently completing a phase IIb, multi-center RCT on its TG4010 (MVA-MUC1-
IL2) vaccine for treatment of advanced NSCLC. Transgene recruited 140 patients with stage
IIIB/IV locally advanced or metastatic NSCLC to compare the efficacy of TG4010 plus
chemotherapy against chemotherapy alone. The primary outcome measure is progression-free
survival at 6 months. Secondary measures include response rate, time to progression, overall
survival, safety, immune response, and proteome profile. The company's website indicates that
preliminary results will be announced in the fourth quarter of 2007; however, no results are yet
available. Transgene's estimated completion date for this study is around December 2009.
At the 2005 ASCO annual meeting, Transgene announced final results for its phase II, multi-
center, two-stage RCT, which led to the trial phase IIb trial described above. The study was
designed to compare the efficacy of TG4010 plus chemotherapy (TG/Ch) and TG4010 alone
(TG) followed by TG4010 plus chemotherapy when disease progressed. Sixty-five patients,
including 15 with stage IIIB NSCLC and 50 with stage IV NSCLC, were enrolled. From the
beginning, patients in the TG/Ch group received concurrent treatment with TG4010, cisplatin,
and vinorelbine. Patients in the TG group received TG4010 alone until signs of disease
progression, and then received TG4010 plus cisplatin and vinorelbine for the remainder of the
study. In the TG/Ch group, 37% showed a partial tumor response to treatment, and 68% showed
disease control at 12 weeks with a median time to progression of 6.4 months. In the TG group,
21% showed a partial tumor response to treatment. The TG group did not meet set criteria for
entering stage two of the study. TG4010 treatment was well tolerated; injection-site reactions
were the most common AE related to the drug. TG4010 is also in phase II trials for treatment of
prostate cancer.
EGF-P64/Montanide (Bioven)
Bioven is conducting a phase II/III, interventional RCT on EGF-P64/Montanide (EPM) vaccine
to determine its safety, immunogenicity and efficacy in patients with stage IIIB/IV NSCLC.
Bioven plans to enroll 230 patients in the study, which has a primary outcome measure of overall
survival at 2.5 years. Patients in the EPM group will receive an initial dose of cyclophosphamide
followed by a series of EPM vaccinations and BSC. Patients in the control group will receive
BSC only. Results are not yet available; however, a company news release reports that the EPM
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vaccine has been used in over 320 patients worldwide with measurable success against multiple
forms of cancer. No published trial data are available to confirm these claims.
Effect on Other Technologies
While some TCVs are being developed as monotherapies, most will likely find their niche as
adjunct therapies combined with surgery, radiation, and chemotherapy. TCVs may be used
before, during, or after other treatments to weaken cancer cell resistance to treatment, augment
cytotoxic properties of chemotherapeutic agents or radiation; and/or eliminate cancerous cells
remaining after surgery.
Some vaccine technologies for advanced lung cancer, which have not yet reached phase III trials,
are being developed that utilize the patient's own antigen-presenting cells and/or tumor antigens
to stimulate a stronger, more targeted defense. These developments may further increase the
safety and efficacy of TCVs for lung cancer and prove beneficial to patients with disease that is
refractory to other therapies.
Other immunotherapeutic angles are also being explored, such as the use of monoclonal
antibodies against tumor antigens or cancer-associated molecules. For example, Avastin
(Genentech, South San Francisco, California, USA), a monoclonal antibody against vascular
endothelial growth factor (VEGF), has received FDA marketing approved for treatment of
unresectable, nonsquamous, advanced/metastatic, or recurrent NSCLC.
Selected References
Biomira Inc., Merck KGaA, EMD Pharmaceuticals. Safety study of BLP25 liposome vaccine in
non-small cell lung cancer patients with unresectable stage III disease. [NCT00157196].
[internet]. Bethesda (MD): National Institutes of Health (NIH); 2007 Dec 21 [accessed 2007 Dec
17]. Available: http://www.clinicaltrials.gov.
Brichard VG, Lejeune D. GSK's antigen-specific cancer immunotherapy programme: pilot
results leading to Phase III clinical development. Vaccine 2007;25(2):B61-71.
Butts C, Murray N, Maksymiuk A, Goss G, Marshall E, Soulieres D, Cormier Y, Ellis P, Price
A, Sawhney R, Davis M, Mansi J, Smith C, Vergidis D, Ellis P, MacNeil M, Palmer M.
Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung
cancer. J Clin Oncol 2005 Sep 20;23(27):6674-81.
Nemunaitis J, Nemunaitis J. A review of vaccine clinical trials for non-small cell lung cancer.
Expert Opin Biol Ther 2007 Jan;7(1):89-102.
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Sangha R, Butts C. L-BLP25: a peptide vaccine strategy in non small cell lung cancer. Clin
Cancer Res 2007 Aug 1;13(15 Pt 2):s4652-4.
Tabi Z, Man S. Challenges for cancer vaccine development. Adv Drug Deliv Rev 2006 Oct
1;58(8):902-15.
Transgene. Immunotherapy with TG4010 in patients with advanced non-small cell lung cancer.
[NCT00415818]. [internet]. Bethesda (MD): National Institutes of Health (NIH); 2007 Dec 21
[accessed 2007 Dec 4]. [5 p]. Available: http://www.clinicaltrials.gov.
Vansteenkiste J, Zielinski M, Linder A, Dahabre J, Esteban E, Malinowski W, Jassem J, Passlick
B, Lehmann F, Brichard VG. 2007 ASCO Annual Meeting Proceedings Part I. Final results of a
multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy
of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II NSCLC. [abstract no. 7554].
J Clin Oncol 2007 Jun;25(18S)
Velu T, Ramlau R, Quoix E, Pawlicki M, Pless M, Lena H, Levy E, Krzakowski M, Limacher J,
Bizouarne N. 2005 ASCO Annual Meeting Proceedings. A phase II study evaluating the clinical
efficacy of TG4010 (MVA-MUC1-IL2) in association with chemotherapy in patients with non
small cell lung cancer. [Abstract no. 7132]. J Clin Oncol 2005 Jun 1;23(16S Part I of II)
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