Shaping the future of healthcare: rhetoric in health technology forecasting

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


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


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


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


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.


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.


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.


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


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.


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,


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:


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


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.


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.


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:


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.


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.

http://www.nlm.nih.gov/nichsr/hta101/hta101.pdf

https://www.ecri.org/Pages/default.aspx

http://www.hayesinc.com/hayes/


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.

https://www.ecri.org/Products/Pages/htais.aspx?sub=Forecasting%20and%20Trends

http://www.hayesinc.com/hayes/hayes_insights/

http://www.thrombosisadviser.com/scripts/pages/en/current-treatments/anticoagulants/single-coagulation-factor-inhibitors/index.php

http://www.thrombosisadviser.com/scripts/pages/en/current-treatments/anticoagulants/single-coagulation-factor-inhibitors/index.php

https://www.ecri.org/About/Pages/default.aspx

http://www.hayesinc.com/hayes/about_us/

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.

../../Documents/ECRI%20(Backup)/Misc%20Documents/[email protected]

http://www.ecri.org/

Hulshizer 23


Therapeutic vaccines for prostate cancer


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.


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)

Hulshizer 24


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.


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


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


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.

Hulshizer 27


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


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.

Hulshizer 29


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


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

Hulshizer 31


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.

Hulshizer 32


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.

Hulshizer 33

Combination naltrexone/bupropion for long-term treatment of obesity



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.


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.

Hulshizer 34


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

Hulshizer 36

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.


Hulshizer 37

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.


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.


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.

Hulshizer 38

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.

Hulshizer 39

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.


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



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.


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.


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.


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.


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.


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.


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)

Shaping the future of healthcare: rhetoric in health technology forecasting

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