Originally published as JCO Early Release 10.1200/JCO.2002.04.084 on July 1 2002

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Study of the Media’s Potential Influence on Prospective Research Participants’ Understanding of and Motivations for Participation in a High-Profile Phase I Trial

From the University of Texas M.D. Anderson Cancer Center, Houston, TX; Winship Cancer Institute, Emory University, Atlanta, GA; and Duke University, Durham, NC.

Address reprint requests to Rebecca D. Pentz, PhD, Winship Cancer Institute, Emory University, 1365 B Clifton Rd NE Suite 6200, Atlanta, GA 30322; email: rebecca_pentz{at}emoryhealthcare.org

	ABSTRACT

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PURPOSE: To describe prospective participants’ initial source of information about, understanding of, and motivation to participate in a phase I clinical trial of the antiangiogenesis agent human recombinant endostatin.

PATIENTS AND METHODS: We surveyed 100 of 130 persons referred to the endostatin trial between October 1999 and November 2000 and analyzed media coverage of the agent from 1997 to 2000.

RESULTS: Forty-seven percent of survey respondents first heard about the trial from media reports. Fifty-one percent of these subsequently contacted their physicians. Thirty-three percent of respondents correctly understood the purpose of the trial. Seventy-nine respondents were interviewed before they met trial investigators to discuss the trial. Of these, those who first heard about endostatin from the media were five times more likely to understand correctly the trial’s purpose than those who first heard from other sources. Seventy-four percent (70 of 95) of respondents cited hope for personal benefit as the main reason for their willingness to enroll. Those who first heard about endostatin from the media were no more motivated by hope of personal benefit (77%) than those who first heard from other sources (71%) (P = .46). Ninety-nine percent of all respondents cited "joining the study gives me hope" as a contributing factor in their decision making about the trial.

CONCLUSION: Media coverage prompted prospective participants to contact their physicians but did not seem to hinder understanding nor could it be shown to heighten their hope for personal benefit.

	INTRODUCTION

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THE ANTIANGIOGENESIS agent human recombinant endostatin received extensive media attention, beginning with a front page, above-the-fold, New York Times article May 3, 1998.¹ Although most new drugs receive media coverage based on the results of clinical trials (other recent high-profile drugs, such as Herceptin [trastuzumab; Genentech, San Francisco, CA], Gleevec [imatinib mesylate; Novartis Pharmaceuticals, East Hanover, NJ], Iressa [ZD 1839; AstraZeneca Pharmaceuticals, London, United Kingdom], and Erbitux [IMC-C225; ImClone Systems, Inc, New York, NY], made news only after a clinical trial), the New York Times story about endostatin appeared almost a year and a half before the first phase I trial opened. Medical writer Gina Kolata quoted James Watson, "Judah [Folkman, whose laboratory discovered endostatin] is going to cure cancer in two years," and Richard Klausner, then Director of the National Cancer Institute, "I am putting nothing on higher priority than getting this [endostatin] into clinical trials."¹ These experts later claimed that their comments were more modulated,^2,3 but the retractions seemed to make the event more newsworthy.⁴ When The University of Texas M.D. Anderson Cancer Center became one of three sites for phase I testing of endostatin,⁵ we were concerned that hyperbolic media coverage would exacerbate prospective participants’ misunderstanding of the purpose of a phase I trial^6-8 and heighten their hope of personal benefit^9-11 when the actual chance of benefiting from a phase I trial is small.^12-15

The relationship between the media and science has been thoroughly analyzed and critiqued. Media reports are an important source of information about science for the public, patients, and researchers.^16-18 They affect both consumer behavior^19-22 and research, speeding up the release of drugs, calling attention to fraud, and influencing funding decisions.^16,23-24 Some have lamented this influence, claiming that media reports that meet the journalistic criteria of being concise, new, and dramatic, necessarily distort science that relies on replication and incremental advances.^25-27 Journalists, scientists, and the public each bear some responsibility for miscommunication and misunderstanding.^28,29,23

Some attention has been paid to the harm of reporting research results based on presentations made at scientific meetings^30,31 and to trial participants’ responses to media reports. In the early 1980s, Cassileth’s study on patients’ and public attitudes toward clinical trials was done partly in response to media reports of falsified research data.³² Nevertheless, the influence of the media on prospective research participants is largely unexplored.

	PATIENTS AND METHODS

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Instrument Development
We designed a structured interview based on the Advisory Committee on Human Radiation Experiments’ Subject Interview Study Brief Survey, in consultation with one of the designers (J.S.). The M.D. Anderson institutional review board approved the study. We then pilot-tested the instrument on the first 16 respondents and modified it slightly based on their responses.

Survey of Referrals
The M.D. Anderson endostatin trial investigators accepted referrals only from M.D. Anderson physicians. The faxed referral form asked whether the patient agreed to be contacted about an ethics survey. All but one of the first 130 agreed. We attempted contact between October 1999 and November 2000. We obtained oral consent for surveys conducted in person or by phone; an informed consent statement prefaced written surveys.

Ninety-eight surveys were completed in person or by telephone and two surveys were completed by mail for a total of 100 completed surveys. There were 30 nonrespondents: one whose referral form directed against contact; nine who could not be reached; three who had died or were in a coma by the time of contact; seven who declined to be surveyed; four who failed to return mailed, faxed, or hand-delivered surveys; one whose interview was aborted by the interviewer because the respondent did not understand many survey questions; and five who agreed to participate but, lacking time or energy, did not complete the survey. Because we had consent for participation from only these five of the 30 nonrespondents, we were unable to evaluate potential bias in this group.

Investigator Media Analysis
Using the databases of three daily newspapers that have high-quality science reporting,³³ the Boston Globe, New York Times, and Chicago Tribune, we identified all articles from 1997 to 2000 that mentioned endostatin. One researcher (R.P.) and a research assistant independently reviewed and characterized each article as providing a positive spin, a negative spin, or a factual account of endostatin. Another researcher (M.C.) resolved differences of opinion on 20 articles. We searched the Lexis-Nexis database of major newspapers to determine whether four other recently developed drugs, Herceptin, Iressa, Erbitux, and Gleevec, received pretrial coverage.

Statistical Analysis
Open-ended answers were transcribed verbatim and categorized by two investigators (R.P. and A.F.), with conflicts resolved by a third (M.C.). Associations among categorical variables were tested using the ² or Fisher’s exact test as appropriate. In the absence of a priori categorizations, responses were grouped into binary categories based on equal sample numbers in each group (eg, income, age). Response changes over the enrollment period and multivariable analysis of responses were modeled using logistic regression. These analyses were conducted using the Statistical Analysis System (SAS, Cary, NC). The primary outcome was correct understanding and its relationship to media exposure; secondary end points included motivations for participation, concerns, and demographic variables. Informed consent status for the endostatin trial at the time of the survey was a post priori function of the sampling procedure, and related hypothesis testing with this factor was exploratory. Zelen’s exact test was used to test for homogeneity of odds ratios of first source of information by correct understanding across informed consent strata. Both Zelen’s test and exact confidence intervals for within-stratum odds ratios of first source of information by correct understanding were performed using StatXact 3.0 (Cytel Software Corp, Cambridge, MA).

	RESULTS

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The median age of respondents was 56 years (range, 25 to 79 years), 86% were white, and 69% had at least some college education. The respondents were balanced for sex (51% male and 49% female). Forty-nine percent of respondents reported income of more than $60,000 a year, with one third more than $80,000. The majority of respondents viewed their religious or spiritual beliefs as important: 64% (63 of 98) very important and 21% (21 of 98) moderately important.

Media as a Source of Information
Most of the newspaper stories occurred 18 months before the first clinical trial started. Another wave of coverage occurred as the first clinical trial opened.

Forty-seven percent of respondents reported that they first heard about endostatin from media sources: 18% from newspaper coverage, 13% from televison, 7% from magazines, 5% from the internet, and 4% from unspecified media sources. Three people heard about endostatin from stock market reports or their broker. Fifty-one percent of those who first heard about the endostatin trial from the media then contacted their physicians. Sixty respondents offered their impression from media reports. Of these, 65% judged the reports to be positive. Their comments included, "I wanted to go after it;" "[it was] real promising;" "a ray of hope;" "a major breakthrough;" and "[I was] very impressed. . . wanted to do it right then." Thirteen percent described media reports as factual, whereas 7% (four of 60) expressed concerns.

Our analysis of 126 newspaper articles mirrored respondents’ assessments. Fifty-nine percent (n = 74) gave a positive spin on endostatin, 16% (n = 20) a negative spin, and 25% (n = 32) a factual account. Although the respondents’ impressions and the investigators’ analysis of media were similarly positive, the articles we reviewed did not match all of respondents’ media sources. We, therefore, can conclude only that media reports generally had a positive tone.

Thirty-five percent of respondents first heard about the trial from their physicians. As time progressed and media attention subsided, respondents’ first source of information shifted from the media to physicians.

Understanding the Purpose of a Clinical Trial
At the time of our survey, 79 respondents (79%) had not yet met with endostatin investigators to discuss the trial. We characterized this group of respondents as preinformed consent (pre-IC) to reflect that they had not acquired any information about the endostatin trial directly from its investigators; all of their information came from other sources. Twenty-one respondents were postinformed consent (post-IC) because they had met with the investigators to discuss the endostatin trial in detail before we interviewed them. The post-IC group includes those who had met with endostatin investigators at the time of the survey and, subsequently, either signed an informed consent document for that trial, decided against entering, were found to be ineligible, or were awaiting test results to determine eligibility. The two groups, pre- and post-IC, were comparable in age, race, education, and income.

We asked respondents, "What do you think is the purpose of the investigational study that you will discuss with your physician?" Fifty-seven percent (55 of 97) stated learning whether the drug works, 28% (27 of 97) stated monitoring safety/toxicity/side effects, 11% (11 of 97) stated dose determination, and 10% (10 of 97) stated to cure or make me well (25 mentioned two purposes and three did not respond).

We counted three types of responses as evidencing a respondent’s correct understanding of phase I trial purpose: (1) monitoring drug safety, toxicity, and/or side effects; (2) dose determination; and (3) learning whether the drug works or cures cancer, if the respondent also mentioned safety or dose determination. Although the primary purposes of phase I trials are safety and dose determination, efficacy is monitored. Therefore, we considered the mention of efficacy correct as long as the participant also mentioned safety or dose determination. We acknowledge that dose determination is ambiguous, meaning either "most effective dose," an incorrect answer, or "safest dose," a correct answer. Because we considered dose determination to be correct, our number of correct respondents may be inflated.

According to this assessment of correctness, 33% (32 of 97) of respondents correctly understood the purpose of a phase I trial. These respondents were predominantly white, younger than the median age of 56, with some college education. In this sample, those who had met with trial investigators were no more likely than other respondents to identify trial purpose correctly. Table 1 lists the groups with correct understanding.

Motivation and Reasons for Participating
We asked respondents about their motivation in two ways. First we asked, "What is the main reason you are willing to participate in the trial?" Responses are shown in Table 3. Because hope for personal benefit was the most frequently cited motivation, we further analyzed this variable. Hearing first about endostatin from sources other than the media, correctly understanding the purpose of the trial, and having discussed the trial with investigators were not significantly associated with a lower number of respondents hoping for personal benefit. The only significantly correlated variable was "holding one’s religious beliefs to be very important." Table 4 lists these results.

Respondents expressed a positive attitude toward research. When asked the impact of enrolling onto trials like this one on cancer patients’ "overall sense of well-being," 47% answered "some improvement" and 19% answered "a great improvement." Only 2% thought trial participation would worsen a cancer patient’s sense of well-being.

	DISCUSSION

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For those interviewed, the media were a powerful information source and motivator for prospective endostatin trial participants at M.D. Anderson. Almost half of respondents (47%) had heard about endostatin first from media sources, and 51% of these subsequently contacted their physicians to learn more about it. Despite its positive tone, media attention did not exacerbate prospective participants’ misunderstanding of the trial’s purpose. Almost half (44%) of those who first heard from the media correctly understood the purpose of the trial. In fact, of the pre-IC cohort who heard first about endostatin from the media, 47% correctly understood the purpose of the trial, a significantly higher percentage than the pre-IC respondents who first heard from other sources (15%, P = .003). Because we did not query respondents about all their sources of information, we cannot conclude to what extent the information provided by the media was responsible for this level of understanding.

Although others have not found correlations between correct understanding and demographic variables among participants in phase I trials^7,10 other than higher education level,^6,9 we found three correlations: age under the median of 56 years, being white, and having some college education.

Meeting with trial investigators to be informed about the trial resulted in no detectable impact on correct understanding of the trial’s purpose. There were, however, slight differences between the pre- and post-IC cohorts that suggest effects the IC process may have on understanding. No post-IC respondent, compared with 10 pre-IC respondents, believed that the trial was designed to "cure my own cancer." Only one post-IC respondent, compared with 11 pre-IC, reported ignorance about the purpose of the trial, and the only respondent who was not aware that endostatin was investigational was pre-IC. The overall percentage (33%) of respondents who correctly understood the purpose of the trial was similar to that found in previous studies of phase I participants, which report between 33% and 43% with correct understanding.^6,9,10 These other studies queried participants after they had given informed consent to participate, whereas most of our respondents had not yet been informed by trial investigators, pointing again to the lack of effect of the IC process.

The high percentage (79%) of pre-IC respondents who said they were willing to participate in the trial supports the observation by Gordon and Daugherty that "many patients begin to make the decision to enter clinical trials before any formal discussion (and subsequent written informed consent) with the clinical investigators conducting phase I trials."³⁴ Whether respondents believed they had gleaned enough information from sources other than the investigators or because investigators’ information was not crucial to their decision, the decision to participate relied primarily on other bases.

The role of hope in our respondents’ decision making was remarkably high, rendering the effect of positive media attention difficult to discern. Seventy-four percent of respondents spontaneously offered hope as their motivation for participation in response to an open-ended question, and an overwhelming 99% of respondents affirmed that hope contributed to their decision to participate. The discrepancy between participants’ hope for and the small chance of personal benefit from phase I research has been a major ethical concern. Various theories have been offered to explain this discordance, including incomplete informed consent,⁶ protective psychological mechanisms among participants,^35,36 researchers leaving room for hope,³⁷ and researcher and participant collusion in misunderstanding.³⁸ One researcher declared the disconnection inexplicable.¹⁰ Proposed solutions include redesigning phase I trials to increase efficacy,^15,39 and improving the informed consent process.^36,40 Still others suggest that forcing participants to understand better their limited options may in fact harm them by destroying treatment-specific optimism.³⁵

Our data, which showed that respondents who correctly understood the purpose of the trial were just as likely to be motivated by hope of personal benefit as those who misunderstood the purpose, support the coexistence of correct understanding of trial purpose and treatment-specific optimism. This result stands in contrast to Daugherty et al⁶ and Rodenhuis et al,¹¹ who found misunderstanding correlated with expectation of personal benefit. However, assuming correct understanding carries with it recognition that the trial offers little chance of benefit, our data support Howe’s³⁷ thesis and Cohen et al’s³⁵ conclusion that even when participants acknowledge the low probability of benefit from phase I trials, the possibility allows them to remain hopeful. Two respondents’ comments are illustrative: ". . . phase I is strictly to figure out dosage and side effects. Objective is not to cure patient. Naturally [I am] hopeful it will"; and "[This is a] phase I so strictly to determine dosage. . . I know this illness is going to kill me, but the fact that I’m doing treatment that might have a negative impact on cancer improves my ability to function, gives me positive energy. My doctor’s worried that this is false hope. It’s NOT false hope; I’m participating in taking steps, in helping my life be as valuable as it can be for as long as possible." This attitude is consistent with respondents’ view that participating in trials like this one improves one’s overall sense of well-being.

Those who understand that personal benefit is not the purpose of the trial but who remain hopeful that it will benefit them constitute an ethically desirable phase I research population, for this group avoids both false hope and hopelessness. We also suggest two additional conclusions. First, the presence of hope for benefit among respondents who accurately understood the nature of a phase I trial undermines the argument that offering seriously ill patients the truth about their health care options deprives them of hope. Second, if, as our data suggest, correct understanding can coexist with treatment-specific optimism, improving the informed consent process, as ethically important as this is, may not change participants’ motivations from self-oriented to altruistic. In any case, our respondents’ clear communication that research offers hope substantiates a general perception that the elusive chance of cure and the opportunity to keep fighting draw patients to seek investigational approaches to treat their diseases, even among patients who correctly understand the low probability of personal benefit from a phase I trial.

Our findings do not alone justify offering experimental interventions to combat patients’ hopelessness and despair, in part because we did not evaluate whether respondents fully understood their healthcare alternatives, including palliative care. Our conclusions are limited in several other respects. A sampling bias is possible because we do not know if the 30 nonrespondents differ significantly from respondents. Beyond limitations related to the post priori nature of the pre- and post-IC variables, our post-IC cohort was small, making comparisons between pre- and post-IC cohorts tentative. Other cohorts were small as well, with only 47 persons first hearing about endostatin from the media. Further, because the respondents were referred to one phase I trial conducted at one cancer center, our conclusions may not be generalizable to other research populations. Our respondents were largely white, had higher family income (United States median family income, $49,600; 39.6% more than $60,000), were better educated than the national population (17% had postbaccalaureate degrees compared with 7.5% in the United States Census 2000, United States Census Bureau; available at http://factfinder.census.gov), and may also be atypical for phase I trial participants.

Our concerns that hyperbolic media reports of a new agent, not yet tested in humans, would magnify misperceptions among prospective participants were not supported by our data. Hearing about endostatin first from the media did not seem to exacerbate patient misunderstanding and may have improved understanding. Nor could we show that the media as a source of information inflated hope, which virtually all respondents exhibited. Our data does show that media coverage sparked patient interest in the endostatin trial. As we know from our own experience and accounts from other centers doing phase I endostatin research, this prospective participant interest strained normal accrual mechanisms. Recognizing this influence, we urge modulated reporting on preliminary research to limit related burdens such as costly lotteries and special referral mechanisms. Because positive media reporting can increase demand for trial participation, we must also be concerned that negative media may lower accrual to trials of promising agents. Yet, we can also applaud the media’s potential to increase participant understanding. Discussion in the research community about fair and cost-effective access to investigational agents should continue.

	ACKNOWLEDGMENTS

 
Supported in part by a grant no. U01 CA62461 from the National Cancer Institute, Bethesda, MD.

This article was published ahead of print at www.jco.org.

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Submitted April 10, 2002; accepted June 11, 2002.

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