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During the past decade, spending on patient recruitment programs has grown 16% annually. In that same period, volunteer randomization rates have declined.
Last year may well be remembered as a public relations nightmare for the clinical trials industry.
Early in 2004, the American Medical Association and the publishers of prestigious, peer-reviewed medical journals such as the New England Journal of Medicine called for a government-based clinical trial registry to provide greater disclosure of drug risks in order to address potential bias in industry-sponsored clinical trials. That same month, the New York attorney general filed a lawsuit against GlaxoSmithKline for deliberately suppressing negative clinical trial results for its antidepressant drug Paxil. Dr. Angell's controversial and highly publicized summer 2004 book, The Truth About Drug Companies: How They Deceive Us and What to Do About It, argued that conflicts of interest guide industry-sponsored trials.
Later in the year, Merck withdrew its blockbuster COX-2 inhibitor Vioxx due to the drug's elevated risk of heart attacks shown in a large clinical trial. The Office of the Inspector General next released a survey showing that one-third of FDA scientists have doubts about the agency's ability to monitor the safety of new therapies during the review and approval process. And late in 2004, clinical research results showed elevated risk of heart attack and stroke with Pfizer's widely used COX-2 inhibitors Celebrex and Bextra. The press also reported on one study suggesting increased risk of cardiovascular events with over-the-counter drug Aleve.
Poor public relations in 2004 are arguably part of a longer, five-year downward spiral that the clinical trials industry has endured and largely ignored. Indeed, some of the media's scrutiny and skepticism has been warranted. In 1999 and 2000, several tragic deaths of study volunteers participating in government- and industry-funded clinical trials (e.g., Gage Stevens, Jesse Gelsinger, Ellen Roche) were widely publicized. In 2001, the Office of the Inspector General released a report documenting a stretched and failing human subject protection system. That same year, the Food and Drug Administration reported dramatic increases in the number of complaints filed against investigators for noncompliance and fraud. In 2002, the Institute of Medicine issued its report calling for major reforms to the informed consent process.
An assessment of major newspaper coverage during the past five years shows that the frequency of articles on the clinical research enterprise is increasing, but the number of negative articles is growing at a disproportionately faster rate.1 In 2002, Time Magazine published its now-famous cover story "How Medical Testing has Turned Millions of Us into Human Guinea Pigs." The media's reference in this article—and in dozens more since then—to study volunteers as "Guinea Pigs" fails to acknowledge the profound decision that millions of people make each year when they give their consent to participate. The article also neglects to report that volunteers are active participants in a study and that they have the option to withdraw at any time. Sadly, clinical research professionals in government, foundations, and industry have done remarkably little to address the media's incomplete, sensationalistic, and ill-informed portrayal. Yet the public and prospective volunteers derive most of their exposure to—and education about—the clinical research process from the media.
Public and volunteer communities know nearly nothing about clinical research and the important role that each party plays in the process. Historically, the clinical research community has relied heavily on the informed consent (IC) process as the primary means of educating study volunteers. Not only is the IC process reaching a narrow subset of the communities that it must educate, but also recent assessments of the process show that it is failing to live up to its intended purpose. According to a 2002 report, for example, the Institute of Medicine found the focus of the IC process to be largely the review of lengthy and confusing documents designed to protect the investigative site from liability.
Although the informed consent process invites study volunteers to ask questions freely, more than 70% of volunteers say that they do not even know what questions to begin to ask. Following informed consent form review, more than 85% of volunteers claim to understand the duration of the study and that they can withdraw at any time. But one-third of volunteers report that they did not understand that their clinical trial may carry additional risk and discomforts compared to a standard treatment.2 Only 17% of volunteers report that they sought input from other trusted sources. And 14% of volunteers say that they did not even bother to read the informed consent document prior to signing it.3
The public and prospective volunteer communities also derive some education about the clinical research process through seeing study advertisements and promotions. According to a 2004 poll of nearly 6,000 adults, more than two-thirds (69%) were exposed to information on clinical research studies through television, radio, print media, and via Internet advertising. One out of seven adult Americans are exposed to information about clinical research studies from their primary or specialty care physician.4 Without broad understanding and context, however, recruitment advertising and promotional messages are met with at best passing curiosity from the public and prospective volunteers. According to recent public opinion polls, 94% of Americans perceive that clinical research is important to advance medical knowledge, but less than 20% of those diagnosed with severe and life-threatening illnesses report considering clinical trials as a health care option.5 Despite a wealth of online information available today, less than 5% of the general public knows where to find information about relevant clinical trials.6
The medical and health professional communities are largely absent from educating the public and prospective volunteer communities. Of the 700,000 board-certified physicians in active community practices, less than half report referring their patients into clinical trials with an average referral rate for each physician of less than one patient per year.7 In 2004, less than 10% of the total number of volunteers completing clinical trials came directly from physician referrals. This is primarily due to health providers lacking adequate information and context with which to make informed decisions on behalf of their patients.8
Growing coverage of the clinical research enterprise in the media is highly problematic. Whereas research sponsors and investigators tend to communicate with journalists when they are ready to announce a medical breakthrough, the media tends to focus on human mistakes, concealment, fraud, and corruption. As a result, there is a long-standing disconnection between the media and clinical research professionals.
Most journalists have little to no formal knowledge about clinical research and they have virtually no time to learn as they rush to meet tight editorial deadlines. Facing a crunch, and due in part to patient privacy and confidentiality, many journalists must resort to interviewing the same study volunteers featured in past articles—typically the ones who are most vocal and often the whistle-blowers. Reporters are often looking for a hook—a storyline that will catch the reader's attention, possibly even garner a journalistic award. Many have been trained to dig for the negative stories and exposés.
Research sponsors rarely, if ever, respond to media coverage as government and corporate employees are usually instructed not to interact with the media for fear of bringing more attention to a story, or of appearing defensive and self-serving. As a result, the public is largely receiving a one-sided view of the clinical trials industry in the media.
Popular culture is also unbalanced. In those rare instances when clinical research is depicted in novels and in film, it is typically portrayed as clandestine and corrupt.9 These portrayals provide the necessary vehicles to create thrilling and intense fiction. In John Le Carre's book The Constant Gardener, for example, a health care activist is murdered before she is able to expose a large pharmaceutical company that has been exploiting vulnerable African study subjects. And in the film The Fugitive, Harrison Ford plays a physician wrongly accused of the murder of his wife. Ford is able to exonerate himself when he proves that the murder was part of a cover-up by a colleague who has been falsifying clinical research data to support a drug for a company in which he is a major shareholder.
Without public education, support, and involvement, research sponsors and investigative sites are spending ever higher levels of resources on patient recruitment and retention with marginal—if not diminishing—results. During the past decade, spending on patient recruitment programs by investigative sites and research sponsors has grown by 16% annually, reaching more than $500 million in 2003.
In that same period, volunteer randomization rates have declined steadily. According to reports from several hundred investigative sites and analyses of study completion records, nearly 45% of volunteers were enrolled in clinical trials in 1984. In 2003, randomization rates declined to less than 25%.
And whereas one out of every six enrollees dropped out of clinical trials in 1984, an average of 27% dropped out of clinical trials in 2003
(see Figure 1).
Figure 1. The recruitment and retention challenge.
Presently, investigative sites report that more than 90% of all clinical trials must extend their original study timelines in order to enroll the requisite number of volunteers.13 Sites attribute these enrollment delays to both the unrealistic timelines set by research sponsors and to the high level of difficulty in recruiting and retaining study volunteers.
Government and industry-funded research sponsors now expect significant project delays as they seek approximately 2.6 million study volunteers to complete their studies each year.14 It is estimated that only 4%-6% of eligible patients who suffer from severe and life-threatening illnesses take part in U.S. clinical trials today.15
Clinical research sponsors have turned their attention to recruiting volunteers from markets abroad—typically from ascending regions that include Latin America, Central and Eastern Europe, India, and China. These regions offer well-trained professionals, large numbers of treatment-naÃ¯ve and motivated patients, and lower relative costs. During the past five years, clinical research spending in ascending regions has grown by 45%-60% annually.16 But sponsors have done a poor job of explaining these strategies and practices to the media and the public. As a result, the media tends to portray the conduct of clinical trials overseas as exploitive and financially motivated.
Regulatory agencies and the clinical research community have responded to public confusion and concern by implementing reforms designed to assure higher levels of compliance and reduce errors that might result in physical and ethical harm to study volunteers. Since 2001, a growing number of universities have established clinical research degree programs. The Department of Health and Human Services has implemented new privacy and conflict-of-interest disclosure guide lines. Two agencies—The Association for the Accreditation of Human Research Protection Programs and the Partnership for Human Research Protection—were established to accredit institutional review boards. In addtion, trade groups including the Drug Information Association and the Association of Clinical Research Professionals have developed investigator certification programs.
This past year, prompted by GSK's alleged failure to disclose clinical research information about Paxil and Merck's withdrawal of Vioxx, public and policy-maker outcry for greater transparency and comprehensive disclosure of active clinical trials and study results came to a head. Industry sponsors, including Eli Lilly, GlaxoSmithKline, and Pfizer, announced programs to provide comprehensive listings of clinical trials online. The industry lobbying group PhRMA (Pharmaceutical Research and Manufactures of America) also launched a clinical trial results Web site.
These reforms and measures are an important step, but they are not nearly enough. They begin to address the need for greater transparency and disclosure, and they satisfy regulatory agency and research sponsor requirements to minimize potential errors, noncompliance, and fraud. However, they fail to acknowledge and address the fundamental need to educate and engage the public and prospective study volunteers. As such, these reforms will only be marginally effective until these communities understand why they are necessary and how they will influence and inform decision-making about the risks and benefits of clinical research participation and new medical therapies.
Recent polls conducted among more than 5,800 American adults suggest that public trust in the clinical research enterprise is waning, with the highest levels of distrust existing among minority communities.
(see Figure 2). The clinical trials industry must act now if it is to better inform and engage the public and prospective volunteers as partners in this process.
Figure 2. Ethnic differences in perceptions of clinical trial safety.
Long overlooked, the clinical research enterprise must proactively raise the overall level of public awareness, must properly and fully inform the public and prospective volunteers, and must establish and build a stronger connection with the many vital stakeholders on the periphery. Broad outreach and advocacy are critical practices that must be utilized to raise public awareness and understanding of the clinical research process and the benefits it brings society.
Outreach and advocacy programs are already being used by a small but growing number of investigative sites and contracted clinical service providers to support patient recruitment efforts. Examples of typical "grass roots" initiatives include clinical research professionals attending health fairs; providing free health screenings at community centers; listing trials in health association and health support group newsletters; and speaking at community events.
Reports on the results of these efforts show that advocacy and outreach has the potential to dramatically impact prospective volunteer interest in study participation. Community outreach efforts have been shown to more than double the rate of prospective volunteer inquiries in a closed head injury study; nearly quadruple the inquiry rate in a recent study of ulcerative colitis; and increase physician referral rates by 71% on a study of a new medical therapy for type II diabetes.18
Current outreach and advocacy programs are promising but limited. They are project specific and therefore not designed to provide a general education. They are short-term in their focus as they are intended to fill individual clinical trials. Once enrollment targets have been reached, these programs are terminated. Their design and implementation also vary from project to project. As such, they fail to provide a consistent and coordinated message.
To be effective and successful, broad education, outreach, and advocacy programs must have the support of the entire clinical research professional community. These programs must be well-coordinated and integrated into all clinical research activities. They should have a consistent message and should focus on raising awareness and engaging stakeholders on the periphery of the enterprise, including the medical community, government officials, family and friends of potential volunteers, and the media.
Specifically, a comprehensive, focused set of initiatives is needed to introduce the public, prospective volunteers, health professionals, the media, and policymakers to the large amount of clinical research activity being supported and conducted within the community each year. These initiatives should include:
1) Educational material to assist volunteers in framing the questions to ask of the research community in order to protect their safety and rights, and to inform the profound decision to participate in a clinical trial. These materials should also address the unique educational needs of special populations (e.g., pediatric and geriatric populations; communities of color and gender-based populations).
2) Broad-based outreach and advocacy programs to convey the important role that health care providers play as partners in the clinical research process. These programs should also assist the media and policymakers in understanding the processes and requirements of developing new medical interventions and participating in clinical research.
3) Messages and images that put a face on the many professionals who dedicate themselves to managing and conducting clinical research and elucidate why R&D is a lengthy, costly, and labor-intensive process that holds the potential to significantly benefit and improve public health.
4) Most importantly, an open acknowledgement of society's appreciation for the many people who give the gift of participation each year.
The National Institutes of Health and the Food and Drug Administration are increasingly recognizing the critical and timely need for broad education, advocacy, and outreach. This past year, the NIH announced the creation of a Public Trust Initiative to instill higher levels of public confidence in government-funded clinical research.19 The FDA recently announced its interest in raising overall awareness of the importance of clinical research to public health and the role that the agency plays in that process.20 In an effort to increase the transparency of industry-funded clinical trial results, PhRMA also recently launched a new Web site21 that includes educational information for the public.
In March of 2004, the Center for Information and Study on Clinical Research Participation (CISCRP) was established to educate and inform stakeholders including the public, prospective volunteers, health providers, policymakers, and the media. Based in Boston, CISCRP is an independent, nonprofit organization that derives its funding from a diverse base of supporters that includes government agencies, foundations, corporations, and individual clinical research professionals. As a result, CISCRP is well-positioned to provide broad education, advocacy, and outreach across all areas of government- , foundation- , and industry-funded clinical research activity.
Since its inception, CISCRP has produced and released the nation's first public service announcements for radio, television, and print to raise awareness and national pride in the clinical research enterprise, and to express appreciation for the millions of people who volunteer to participate in clinical trials each year. CISCRP has compiled contact lists of professionals and experienced study volunteers who have given their consent to speak at community events, lecture medical schools, and be interviewed by the media. It has hosted and participated in numerous advocacy, professional, and community events where broad-based educational materials have been distributed. CISCRP has organized and implemented a Clinical Research Public Perception Summit that brought together members of the clinical research community and the media. The organization was selected to collaborate with the FDA and the NIH on general outreach and advocacy projects. And CISCRP developed and launched a resource-rich Web site at www.ciscrp.org. These are but a few examples of CISCRP's many programs and initiatives.22
It is time for clinical research professionals to acknowledge that the public and volunteer communities have a severely limited and incomplete understanding of the clinical research process, and the important role that each party plays in that process. These stakeholders, and others on the periphery of the clinical research enterprise—including health care providers, the media, and policymakers—are not engaged in the process. Broad education, outreach, and advocacy are needed at both the national and local levels if we are to partner with these vital stakeholders in order to safely realize the profound benefits of biomedical research to society.
An Industry in Evolution: Sourcebook of Charts and Statistics Providing Analysis and Insight into the Clinical Trials Industry
, M. Lamberti, ed.,
, 209 (2002).
2. K. Getz, "The Informed Consent Process," Applied Clinical Trials, 11 (11) 30-36 (November 2002).
3. K. Getz, "The Informed Consent Process," Applied Clinical Trials, 11 (11) 30-36 (November 2002).
4. HarrisInteractive, "Views and Attitudes of Clinical Research Studies," HealthCare News, 4 (15) (May 2004).
5. HarrisInteractive, "Views and Attitudes of Clinical Research Studies," HealthCare News, 4 (15) (May 2004).
6. K. Getz, "Survey of 1,170 Adults at the Clinical Trial Congress in Philadelphia," Institute for International Research (February 2004).
7. D. Borfitz, "Will Physicians Refer their Patient into Clinical Trials?" CenterWatch Monthly Newsletter 11 (3) 5-7 (March 2004).
8. D. Borfitz, "Will Physicians Refer their Patient into Clinical Trials?" CenterWatch Monthly Newsletter 11 (3) 5-7 (March 2004).
9. S. Endo, When I Whistle (Taplinger Publishing Company, 1974); J. Le Carre, The Constant Gardener (Simon and Schuster, 2001); and J. Grisham, The King of Torts (Bantam Dell, 2003).
10. K. Korieth, "Taking Patient Recruitment In-House," CenterWatch Monthly Newsletter, 11 (2) 6-7 (February 2004).
11. K. Getz, "Benchmarking Patient Recruitment and Retention in Clinical Trials. A Guide to Patient Recruitment and Retention," CenterWatch, 25-28 (2004).
12. V. Gamache, Minimizing "Volunteer Dropout," CenterWatch Monthly Newsletter, 9 (12) 9 (December 2003).
13. K. Korieth, "Taking Patient Recruitment In-House," CenterWatch Monthly Newsletter, 11 (2) 5 (February 2004).
14. National Institutes of Health Report, "Monitoring Adherence to the NIH Policy on The Inclusion of Women and Minorities as Subjects in Clinical Research," C. Roth and V. Pinn, Co-Chairs (September 2000); and the PAREXEL Pharmaceutical R&D Statistical Sourcebook, M. Mathieu, ed., 105-110 (2003/2004).
15. E. Paskett et al., "Clinical Trial Enrollment of Rural Patients with Cancer," Cancer Practice, 10 (1) (January/February 2002); "Monitoring Adherence to the NIH Policy on The Inclusion of Women and Minorities as Subjects in Clinical Research," C. Roth, and V. Pinn, Co-Chairs (September 2000); and the PAREXEL Pharmaceutical R&D Statistical Sourcebook, M. Mathieu, ed., 105-110 (2003/2004).
16. K. Getz and S. Zisson, "Shifts in the Foundation of Drug Development," CenterWatch Monthly Newsletter, 11 (1) 8 (January 2004).
17. HarrisInteractive, Views and Attitudes of Clinical Research Studies, HealthCare News, 4 (15) (May 2004).
18. Analyses of results of recruitment programs conducted by D.Anderson & Company and the Matthews Media Group (2004).
19. To view the NIH report on Enhancing Public Input and Transparency in the National Institutes of Health Research, visit http://copr.nih.gov/enhancing.pdf
20. Drug Information Association Annual Meeting, Washington DC 2004.
21. For more information about PhRMA's efforts to communicate clinical trial results, go to http://www.phrma.org/mediaroom/press/releases/30.06.2004.427.cfm
22. For a detailed description of CISCRP programs and to view the national public service announcement, go to www.ciscrp.org
Kenneth Getz,* MS, MBA, is a research fellow at the Tufts Center for the Study of Drug Development and the founder and chairman of the recently established nonprofit organization Center for Information and Study on Clinical Research Participation, both in Boston, MA, (617) 590-4175, email: firstname.lastname@example.org. James Kremidas is the director of global enrollment optimization at Eli Lilly and Company and co-chair of the Patient Recruitment Sub-Committee for the Drug Information Association, Indianapolis, IN, (317) 276-3483, email: email@example.com.
*To whom correspondence should be addressed.
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