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Patient recruitment for clinical trials is one of the most significant bottlenecks in drug development. As a result, several organizations have called for the establishment of recruitment best practices, beginning in 2000 with the Office of the Inspector General's (OIG) report on recruiting human subjects and most recently in a Clinical Research Roundtable report published in the March 12, 2003 issue of the Journal of the American Medical Association (JAMA).
Patient recruitment for clinical trials is one of the most significant bottlenecks in drug development. As a result, several organizations have called for the establishment of recruitment best practices, beginning in 2000 with the Office of the Inspector General's (OIG) report on recruiting human subjects and most recently in a Clinical Research Roundtable report published in the March 12, 2003 issue of the Journal of the American Medical Association (JAMA). (See "Call to Action," page 66.)
BBK Healthcare has responded with an initiative called Good Recruitment Practice. With the help of an advisory board, the consultancy hopes to have a draft available later this year with the eventual goal of having the guidelines adopted as an industry standard. This article outlines the problems that led to the need for such practices and highlights the various issues the GRPs will cover.
The pharma industry is under intense pressure to produce new drugs, yet development timelines are getting longer and costs are skyrocketing. According to a study from the Tufts Center for the Study of Drug Development, average clinical phase times for new biopharmaceuticals increased by 137 percent (from 31.2 to 74.0 months) between 1982 and 1989 and 2000 and 2002. Pharmaceutical Researchers and Manufacturers of America (PhRMA) reports that between 1998 and 2002, R&D spending rose from $21 billion to $32 billion, yet the number of new drugs approved dropped from 35 in 1999 to 17 in 2002.
With those trends, it is no surprise that the clinical R&D industry's needs can be summed up as "faster, better, cheaper." And there is little debate that improving the recruitment of clinical study participants provides fertile ground for meeting those goals. According to CenterWatch, more than 80 percent of clinical trials fail to enroll on time; 44 percent are delayed by one to six months. Time is money. According to Tufts, cutting one year from Phase III studies would save $71.4 million in the total cost of a new drug.
Yet, slow development times are just symptoms of more deeply seated patient and investigator recruitment problems. According to McKinsey & Company, 85–95 percent of all days delayed during clinical trials is a result of a failure to recruit patients on time. Obstacles to recruitment are complex and multifaceted:
Critical need. The average number of clinical studies per new drug application rose from 36 to 75 between 1985 and 1988 and 1996 and 2000, according to Parexel and the MediciGroup. In the same period, the average number of patients per NDA rose 50 percent, from 3,233 to 4,850. CenterWatch predicts that, to meet expected demand, the number of respondents to clinical study promotions will have to increase sevenfold, from 2.8 million in 1999 to 19.8 million by 2005. While the level of public awareness and trust in the clinical research enterprise remains lukewarm at best, that is a tall order.
Lack of awareness. Many patients do not know they can participate in clinical trials and would benefit from general education about the research process.
A 2001 BBK/Harris Interactive survey showed that although 83 percent of Americans are willing to participate in clinical studies, only 13 percent do. The same holds true even in oncology. Fewer than 5 percent of adult cancer patients participate in clinical studies. A 2002 survey by a coalition of national cancer groups reveals why: eight of 10 cancer patients were unaware that participation is an option.
Staff problems. Investigator and clinical staff participation is also at issue. From an investigator's point of view, clinical research has become less appealing for a variety of reasons, ranging from the complexity of budgeting and contracting to increasing legal and regulatory concerns. CenterWatch predicts a 15 percent investigator shortfall by 2005. At the same time, referring physicians, who are often crucial for meeting enrollment goals, have both a need for more information about available studies and reservations about losing patients to study investigators.
Risks and benefits. Meanwhile, news reports tend to focus on the triumphs of medical breakthroughs and the tragedies of clinical research. Media, as an audience, need education materials to help them describe the risks and benefits of clinical study participation. When spokespeople from the clinical research community make connections with the press and offer themselves as resources, the resulting stories are more likely to reflect balance-as in Jane E. Brody's "Ferreting for Facts in the Realm of Clinical Trials," published in the New York Times, October 15, 2002.
Informed consent. This process continues to pose an obstacle to patient recruitment and retention. A May 2002 CenterWatch survey found that 10 percent of volunteers did not look at the informed consent form before signing it; 18 percent signed without input from their personal physician, nurse, family member, or trusted advocate; and 70 percent reported that, at the outset of the informed consent process, they didn't know what questions to ask. Improving the communication involved in informed consent should increase study participant compliance.
Money and conflict of interest. Investigators and sponsors face additional challenges when it comes to compensation structures and potential conflicts of interest. A survey review of 37 studies by Bekelman et al. in the January 22, 2003 issue of JAMA reported a statistically significant association between industry sponsorship of a clinical study and conclusions that support the sponsor's product. Trial incentives must be carefully designed to avoid conflicts of interest.
Patients versus participants. The dual role of investigators who also serve as treating physicians presents another potential conflict of interest. Physicians in that dual position have a responsibility to clarify their roles for patients, who are often confused about the nature of clinical research. A recent study in the Lancet found that nearly a third of clinical trial participants didn't know the study might not help them. And nearly three-quarters failed to understand that the study was investigating nonstandard treatment. Another two-thirds didn't know they might face additional risks or discomfort. Disclosure of all types of potential conflicts of interest will help potential study participants to make fully informed decisions.
To address such diverse challenges, any solution to the bottlenecks posed by patient and investigator recruitment must be equally multidimensional and comprehensive. In particular, it seems clear that guidelines will work only if they simultaneously make recruitment more efficient and more ethical.
Three years ago, the Office of the Inspector General called for "the development of guidelines for all parties on appropriate recruiting practices," stating that "a clearer determination of appropriate recruiting practices would be helpful for all parties-sponsors, investigators, and institutional review boards (IRBs). It is essential that this determination be made cooperatively with industry and the research community."
To that end, BBK Healthcare is developing principles and standards intended to improve both patient and investigator recruitment. Underlying that goal are the assumptions that clinical research studies are a critical part of the care continuum and that all patients should have access to them as healthcare options. All parties involved in conducting clinical studies share the responsibility of enhancing that perception among physicians and patients.
The initiative, called Good Recruitment Practice (GRP), is being carried out with the help of an advisory board composed of representatives from industry and public arenas, including sponsors, physician-investigators, recruitment companies, and patient advocacy groups. BBK Healthcare also plans to present the GRP to a wide array of stakeholders to review and comment on. The long-term objective is for the guidelines to be adopted as an industry-wide standard. Such adoption would support a faster, better, and cheaper clinical recruitment process, thus yielding data of the quality required to evaluate products and secure FDA approvals.
Leading the advisory board is John Yee, MD, MPH, clinical faculty member at Harvard Medical School, who says, "Ultimately, this initiative is about helping patients make well informed decisions about participation in clinical research, a goal shared by all participants across the clinical research enterprise."
Greg Koski, MD, PhD, former director of the Office of Human Research Protections, US Department of Health and Human Services, and now senior scientist at the Institute for Health Policy, Massachusetts General Hospital, is also a member of the advisory board. He says, "The creation of these guidelines is critical, especially because the industry, rather than the government, is taking a lead role. If they could be adopted by the industry as a whole, it would be an extremely positive sign and a major step toward raising the standards."
Specific goals of the GRP initiative are to:
Reduce R&D delays and costs. The need to save time and money in the clinical R&D process is evident. The GRP approach recognizes that patient and investigator recruitment needs are rarely considered early enough in protocol design and development, leading to unforeseen difficulties and costly corrections once the study is underway.
Applying the science of marketing to the science of clinical research at every phase of development can save both time and money. Rather than planning protocol design, investigator recruitment, and patient recruitment as sequential steps, all elements should be considered concurrently to ensure successful study completion.
"We, as an industry, must improve our ability to streamline the clinical research process," says James P. Kremidas, who manages the clinical trial enrollment services division at Eli Lilly and serves as a member of BBK's GRP advisory board. "Enrollment consideration is not typically factored in early enough in the clinical study development process. The primary focus-as it should be-is the scientific validity of the study itself. But we need to understand patients' motivation to be involved in a study to determine if they would will be willing to participate in that protocol structure."
The GRP committee is developing the draft to include principles of study design, planning, and conduct. The guidelines address such critical components as protocol assessment, investigative site selection, investigator and patient compensation structures, and outreach programs that target audiences based on market research analysis. By creating study protocols with patient perspectives in mind and selecting investigative sites through rigorous analysis of market and site criteria that affect recruitment, the likelihood of successful enrollment can be significantly increased.
In addition, the guidelines address the problems of declining investigator and clinical staff participation by outlining compensation packages that support investigative sites in executing the protocol in the most effective manner.
Educate and empower patients. To better communicate with patients and the public about clinical research, the draft GRP recommends principles and standards in patient information and communications, informed decisions, and public awareness and education.
"We feel it is important to spend a lot of time on the telephone communicating with patients before we bring them in," says advisory board member Kathy Geissler, RN, clinical research coordinator at Rockford Gastroenterology Associates, in Rockford, Illinois. "When they come in, we go over the elements of informed consent, so they not only understand their role in the study but have a grasp of what the study is all about. We feel our patients are better informed by participating in this process, and we have a low drop-out rate because of our involvement with them."
Following patient information and communication guidelines would help those conducting studies to ensure clarity, balance, and lack of coercion at every step of the enrollment process-including initial outreach, informed consent, enrollment, screening, study visits, and post-study follow-up. Making potential enrollees feel respected, safe, and fully informed should increase their willingness to participate in clinical research studies.
Particularly important are informed consent procedures, which currently often fail to accomplish their goals. GRP principles expand informed consent to "informed decisions" and educate patients about the clinical research process and the full range of options available to them, both approved and investigational. Studies have shown that patients seldom understand the risks of participating in a clinical study or aren't aware of the safety measures in place to protect them.
The clinical staff at investigative sites must be equally informed. Primed with the knowledge to answer patient questions and expand patient understanding, investigators and study coordinators can enhance patient comprehension. GRP will provide principles and standards for the clinical research community in reaching out to broader audiences including media, healthcare professionals, and the public. The guidance is specific to each audience, providing objectives by which to measure the type and quality of outreach efforts. The more people understand the connection between the clinical research process and the healthcare system overall, the more likely they will be to support and participate in clinical studies.
Support ethical behavior. The clinical research and development industry must address financial and other conflicts of interest in the system. Doing so will have a positive influence not only on investigator ethics and participation but on referring physician participation as well as public confidence in clinical study participation. GRPs will address the ethical issues involved in incentives, disclosures, and relations between investigators and referring physicians.
According to advisory board member Matthew D. Whalen, PhD, president of Chesapeake Research Review, in Columbia, Maryland, "There continues to be a great deal of concern about conflicts of interest, including recruitment. All of us in the clinical research enterprise are, or should be, involved in the solution. The sponsor, CRO, site, IRB, or third party [such as a recruitment or PR firm] faces privacy and coercion issues among other ethical challenges.
"A key part of GRP is improving current standards of recruiting ethically. Additional guidance in the form of best practices is in everybody's interest. And part of developing those best practices is looking at the full range of the personal, social, and professional conflicts of interest-beyond just the financial."
Incentives to all involved parties must follow ethical guidelines to prevent coercion. GRP principles will provide fair and adequate guidelines. When designing compensation structures, sponsors and IRBs should evaluate whether they introduce bias. The guidelines will address bonuses to investigators or referring physicians, financial investments or stock options held by investigators in sponsor organizations, and the degree to which patient compensation supports good patient decisions.
It is essential that investigators make full disclosures to potential participants about the nature of their relationships with sponsors and, if applicable, the dual nature of their role as both physician and investigator. Some IRBs currently require those kinds of disclosures during the informed consent process.
To address physician relations, GRP principles support physicians and investigators in placing patient interests first. Although the majority of study participants are self-referred, many still learn about clinical studies from their physicians. Improving communications between referring physicians and investigators will support that source of study participants.
Just as the conduct of an individual clinical study requires complex networks of communication, so does the recruitment conundrum demand the collaboration of the clinical R&D community, with its many and diverse representatives. The time is ripe for a comprehensive solution to recruitment challenges.
Good Recruitment Practice will provide a platform for the synthesis of the best ideas available from the disciplines of clinical research, marketing science, and health communications. The time and effort spent designing clinical studies that facilitate investigator and patient participation will contribute to successful enrollment, better compliance and retention, and faster development cycles. Ultimately, GRP will benefit patients by increasing their awareness, understanding, and trust in the clinical research and development enterprise.