In recent years, the public's perception of the clinical research industry has eroded to an all-time low. Media coverage of study mishaps combined with the rising cost of prescription drugs have contributed to the growing mistrust between the public and industry. 

A survey conducted by the Kaiser Family Foundation back in 1997 found that 79% of individuals felt drug companies did a "good job" of serving the public. The same survey conducted in 2004 found that a majority of Americans felt for the first time that drug companies did a "bad job" of serving their customers.

  This change demonstrates that the clinical research industry needs to re-establish its credibility to regain public confidence. 

Clinical research is a fundamental process that is necessary to bring safe and effective new drugs to the market for public use. Surveys show that 83% of individuals agree that it is either "essential" or "very important" to test new drugs on humans before they are approved for general use. 

Although the majority of respondents strongly believe that clinical trials are valuable, only 32% feel that participants receive good medical care, and only 13% believe that participants will not suffer more pain or side effects than if they received standard treatment. In addition, only one in four people indicated they are very confident that "new treatments are tested in clinical trials only after there is good scientific evidence that the treatments are likely to be effective and safe,"

  and 62% believe that pharma companies manipulate clinical data.

The perceptions and attitudes of individuals who have participated in clinical research studies are drastically different from the general public's: 90% rate the quality of care they received during a clinical trial as "excellent,"

  and 84% indicate they would participate in another clinical study if given the chance.

  This difference in attitude between the general public and those who have actually participated in research indicates a significant gap between what the general public perceives and the positive experiences of research volunteers. 

In order to regain public confidence, clinicians and industry leaders need to alter their current patterns of industry promotion and media response. They need to become more active in broad-based advocacy and outreach programs, proactively promote the clinical research industry within the health care community, and improve media relations. These changes will help educate the public about the clinical research process by giving them a more complete understanding of the quality of care subjects receive and how they can find research opportunities and information on clinical research studies for which they may be eligible. 

The cost of trials is rising exponentially. In 1997, it was estimated that the cost to bring a new drug to market was $800 million; costs have soared to nearly $1.5 billion today.

  Contributing to rising costs are the longer development timelines required to bring a new drug to market. The average clinical phase time for new biopharmaceuticals increased from less than three years in the 1980s to between six and seven years today, while total R&D spending rose from $21 billion in 1998 to more than $51 billion in 2005.

As mentioned, an increasing number of individuals are growing skeptical of the personal benefits and safety of clinical studies. Of the 50,000 trials taking place in the United States, 80% are delayed at least one month due to unmet enrollment projections.

  This lack of subject participation stems from a variety of sources, including negative media coverage, poor public perception, and a lack of education. Only one in four people feel that trial patients receive honest and accurate information and are not treated like "guinea pigs."

The abundance of information indicating public trust has rapidly declined in recent years helps identify why many clinical studies fail to meet enrollment projections. Robert Kelch of the University of Iowa College of Medicine credits two reasons for why this lack of trust has occurred: insufficient clinical advances compared to public expectations, and social and business trends that have changed the public's perception of health care from a social good to a purchasable commodity. 

In addition, negative events publicized in the media have caused the public to question how well the industry is governed.

  Figure 1 illustrates how public trust in clinical research has drastically declined in recent years. For example, between 1996 and 2002 over 50% of people stopped trusting clinical research information, indicating a major negative shift in the reputation of the clinical research industry. The pharmaceutical industry is now perceived as being as honest as the tobacco, oil, and used car industries.

In response to rising health care costs, industry profits, and fraud, the clinical research industry has received a disproportionate amount of negative media coverage over the past decade—which is where the general public receives the majority of its information. With the exception of significant medical breakthroughs, many stories cover fraud, corruption, greed, and significant safety risks to potential patients. These media stories can play a significant role in how likely a patient is to volunteer for a clinical trial. 

Recent survey results show that 79% of adults think that research participants are taking a gamble with their health and 75% think that research participants are sometimes treated as guinea pigs.

  Ken Getz, founder of the Center for Information and Study on Clinical Research Participation (CISCRP), indicates that sites directly involved in clinical study recruitment report that the media directly affects the attitudes of the general public and clinical research participation.

  Getz states in a recent article, "[Industry] has done little to address the media's incomplete, sensationalistic, and ill-informed portrayal" and "most journalists have little or no formal knowledge of research and they have little time to learn." In addition, sponsors rarely respond to media coverage for fear of bringing more attention to a story or appearing defensive and self-serving, which helps contribute to a one-sided view of the industry in the media.

  Thus, clinical research professionals share a portion of the responsibility for poor public perception and will continue to until they proactively promote the benefits of research participation. 

's cover story, "At Your Own Risk," portrayed the industry as treating study volunteers as guinea pigs.

  The article suggests the regulations in place pose a great threat to study volunteers, and institutions and sponsor companies do not have to adequately inform patients of the risks that may be involved. In one example, a research investigator at the St. John Medical Center in Tulsa, Oklahoma, hid safety issues from research participants and failed to report adverse events during a vaccine trial for malignant melanoma. However, the article does not mention the severe penalties that should accompany these actions. According to the FDA 1572 form, failure to conduct a study in accordance with 21 CFR Part 312 and report unanticipated problems involving risks to human subjects is a criminal offense. 

The author also discredits the regulatory framework that governs the industry, stating, "Thanks to a patchy regulatory system, perhaps a quarter of all clinical research—including some studies on reconstructive surgery, dietary supplements, stem cells, and infertility treatments, for example—get no federal oversight whatsoever. And even where oversight is mandated, it's often applied loosely, if at all." Such statements send a message to the general public that they are not being protected, and the industry does not have an effective system in place to ensure that clinical research participation does not impose significantly greater risks than potential benefits. 

Many regulations, laws, and guidelines have been implemented in response to the historical events that have compromised subject safety in the past to prevent such events from recurring in the future. Despite this, the industry still receives an abundance of negative press. Stories of misconduct, such as the death of Jesse Gelsinger in 1999, the unexpected side effects of TeGenero's Phase I biologics study that hospitalized six participants, and the withdrawal of Merck's Cox-2 inhibitor Vioxx, have dominated the headlines, adding to the public's mistrust. These events are not typical in clinical research, but the media portrays them as regular occurrences. 

In 2004, Dr. Marcia Angell attacked the pharmaceutical industry with her book, 

The Truth About Drug Companies: How They Deceive Us and What To Do About It

. Throughout the book, Dr. Angell discusses how the pharmaceutical industry has become corrupt and tries to persuade her audience that it is deceptive and should be distrusted. She calls the FDA "the pharmaceutical industry's favorite whipping boy," as the industry manipulates its way into creating shortcuts in research at the expense of patient safety.

Her claims suggest that the industry routinely suppresses negative results and designs trials that favor the investigational product. Dr. Angell suggests that the industry offers physicians large bounties that can total up to $12,000 per patient. In reality, the average compensation per enrolled study volunteer was $2320 in 2005,

  which typically includes reimbursement for very expensive procedures that must be performed during the course of the study and may not be reimbursed for up to six months. In fact, once investigators pay for their overhead costs, which include a research staff, benefits, facility, and equipment, only a small portion of this fee remains. 

Negative coverage of the research industry has also found its way into popular culture with the release of such movies as 

, which tells the story of clinical research misconduct in Africa and suggests the pharmaceutical industry customarily exploits citizens of underdeveloped countries. The film fails to tell the audience clinical research is governed by an Institutional Review Board (IRB) that oversees the safety and welfare of the study participants. The severe ramifications of attempting to falsify data submitted to the FDA to obtain drug approval are also overlooked. 

Inadequate education is one of the primary factors that has contributed to the lack of credibility in clinical research. The majority of the general public is unaware of the clinical research process and the safeguards the FDA has implemented to ensure subject safety. The FDA is under constant pressure to ensure that drugs are safe and effective for public use, but the public may know very little about FDA regulations, Good Clinical Practice, IRBs, and documents such as the Belmont Report and the Declaration of Helsinki, which outline a code of conduct for clinical research. 

Over the past two years, the reputation of the FDA has suffered: Seven in 10 adults give the agency a negative rating, and 58% have a negative view of its ability to ensure the safety and efficacy of new drugs. The majority of individuals feel the FDA is influenced more by politics than science and does not have the ability to make independent decisions.

Ken Getz suggests that broad education, outreach, and advocacy programs supported by the entire clinical research community are needed.

  In 2004, he founded CISCRP, a nonprofit organization that focuses on increasing community awareness through public service announcements, educational brochures, and an AWARE for All Clinical Research Education and Awareness Day program. 

These Awareness Days have received very high marks from attendees, and a very high percentage of those attending say they would participate in clinical research studies following the program. The programs have been conducted in four cities, but the organization intends to expand this program nationwide and increase its public service announcements to help educate a larger portion of the general public. 

, the Coalition of Cancer Cooperative Groups—sponsored by Amgen, Bristol-Myers Squibb, Pfizer, and The Leukemia & Lymphoma Society—published a special advertising section. It encouraged the public to learn about cancer clinical trials and featured Lance Armstrong. The promotion clarified many of the misconceptions people generally have about clinical trials, including placebos and the level of patient care provided. In the campaign, Armstrong offers the following testimony: "There is a big misconception out there that you will get a placebo in a cancer clinical trial. The reality is that you will receive at least the standard therapy. People need to be aware that they are not going to get a sugar pill instead of treatment." 

Figure 2 shows the results of the 2005 "The Need to Know" survey, which measured participants' experiences in oncology trials. Ninety-two percent of those surveyed reported having a positive experience, while only 9% felt like a "guinea pig."

In addition to the lack of public knowledge, 87% of physicians do not participate in clinical research.

  Many do not have formal training in clinical research or good clinical practice and are unable to adequately inform their patients of research opportunities or appropriately respond to research inquiries. 

A 2003 survey reported that only 16% of adults believe they have ever had the opportunity to participate in a research study.

  Public awareness could be drastically improved if the health care community was more aware of clinical research opportunities. Many individuals mainly rely on their physicians for their health care information. Since only a small number of eligible physicians are currently active in research, a large number of people do not realize they are eligible to participate in research studies. So in addition to expanding the advocacy and outreach programs in the general public community, the industry could also advocate research and increase awareness in the health care community. 

For the public's perception of the clinical research industry to change, health care professionals must believe trial participation is a viable option for patients that can benefit them and the health care community. They must feel comfortable with the level of safety involved in trials before they can recommend participation to patients as a treatment option. 

The clinical research process is a vital component of the pharmaceutical industry, and it is imperative that clinical research professionals do their part to promote the industry, educate the public, and proactively work with the media to portray a balanced image of clinical research. By supporting CISCRP and other advocacy and outreach programs, the industry can begin to reach out to the public. The Pharmaceutical Research and Manufacturers of America can also help lead the industry in raising awareness by promoting campaigns that educate both the public and nonresearch physicians. 

In addition to educational campaigns, our industry leaders need to take more proactive steps to work with the media. Rather than allowing the media to portray an uncontested, one-sided story, we must begin responding to media inquiries and promoting the benefits of the clinical research process. 

Opportunities also exist for the research and development community to become involved in helping shape the reputation of the clinical research industry. Research coordinators, clinical research associates, project managers, and others who have intricate roles in clinical research know first-hand the benefits of clinical research participation. As representatives of the R&D community, they can promote clinical research by communicating its benefits, providing resources for more information, and responding to common questions and misconceptions many people have about clinical trials. 

These are some of the many opportunities the clinical research community has to improve its reputation. The rapid deterioration of our public image serves as evidence that immediate solutions are needed, and the research community must work together to find and implement strategies to reverse the growing trend of public mistrust in research. 

 1. M. Kaufman, "Drugs Get Good Ratings, but Drugmakers Less So," 

 2. H. Taylor and R. Leitman (Eds.), "There are Many Reasons Why People are Reluctant to Participate in Clinical Trials," 

Articles

Feature Article

Who better to educate a wary public about clinical research than the industry's own?

Reach Out to the People

Only 3% of cancer patients participate in clinical trials despite the importance of clinical trials in improving cancer treatment and control. 

The Patient Advocate Sub-Committee (PASC) of the Cancer and Leukemia Group B's (CALGB) Committee on Advocacy, Research Communication and Ethics (CARE), in collaboration with cancer advocacy organizations, surveyed cancer survivors from July to September 2004 to identify how patients learn about and enroll in trials.  

The goal of the survey was to identify opportunities to improve patient enrollment in cancer trials and provide recommendations to improve accrual in CALGB clinical trials. A key challenge to successful cancer clinical trial research is the issue of patient accrual. Poor accrual has been associated with early closure of studies

  Therefore, improving trial enrollment is a priority for NCI-funded research groups such as CALGB. 

The PASC, comprised of patient advocates affiliated with cancer survivor advocacy organizations and advocates possessing skills and experience in clinical research, identified clinical trial accrual as a primary issue to address within CALGB. 

This article presents the findings of the PASC survey and discusses their implications for increasing trial participation among cancer patients. 

The survey assessed awareness of, attitudes toward, and sources of knowledge about cancer trials among cancer survivors; documented the factors associated with clinical trial participation and nonparticipation; and assessed how knowledge, attitudes, and willingness to participate in cancer trials are mediated by demographics, such as ethnicity, socioeconomic status, and education. 

PASC members developed a survey written at an 8th grade reading level, and the CALGB statistical center staff reviewed it. Multiple choice and open ended questions requiring written comments were included in the survey, and written comments were classified and assigned a number code. 

The project was conducted in collaboration with advocacy organizations with which PASC members had ties. Members identified advocacy organizations comprised of cancer survivors who could complete the survey. Each PASC member who identified potential collaborators acted as a liaison to the respective advocacy group. The liaison contacted the advocacy group, explained the project, and assessed the willingness and capacity of the organization to participate. In order to participate, the group needed to inform their membership of the survey and provide access to it. 

Liaisons then worked with each organization to identify the most appropriate mechanism to survey their members. Options included posting the survey on the organization's Web site, mailing out the survey to members along with a newsletter, and administering the survey at a scheduled meeting. 

The CALGB Web site manager established a link to the survey on each collaborating cancer advocacy organization's Web site. Once posted on the site, cancer survivors could click on the link, complete the survey, and then click on an icon to submit it. Once submitted, online survey responses were emailed to the lead author, a PASC member and project coordinator. 

Statistical support staff at Wake Forest University's School of Medicine conducted data analysis. Descriptive analysis was performed on the total sample. Pearson's chi-square tests were used to assess univariate associations of demographic characteristics with clinical trial participants. 

Sixteen cancer survivor organizations were contacted for their interest in participating in the survey, and 14 participated. Most organizations used their Web site to post the survey and inform their members about the study. One organization sent out a mailing in addition to posting the survey, and one circulated the survey at a scheduled meeting. 

A total of 922 surveys were submitted via email, and an additional 35 surveys were mailed in for a total response of 957 surveys over a two-month period. A total of 888 of the submitted surveys contained enough information to analyze, but due to time restrictions, 727 surveys were analyzed. Surveys selected for analysis represented an attempt to maximize demographic diversity, both in type of cancer and ethnicity. 

Most respondents were female (67%), Caucasian (88%), and between ages 50 and 59 (32%) (see Table 1). The most common cancer sites reported by survivors were lymphoma, including Waldenstrom's Macroglobulinemia (WM; 28%), breast cancer (28%), and colorectal cancer (15%). Thirty-five percent of those surveyed reported a cancer recurrence. 

 Table 1. Demographic characteristics of total sample.			

Most respondents possessed a higher education, with 67% having a college degree or graduate degree/training. Fewer than 10% had either a high school diploma or less than a high school education. The majority of survivors reported an annual household income range of $50,000 to $79,000 (30%), and regions within the United States were relatively equally represented. Five percent of participants were from other countries: Canada, the UK, Australia, and Puerto Rico. 

The remainder of the survey addressed respondents' clinical trial participation, as well as knowledge about and attitudes toward clinical trials. Of the total sample, 33% had either entered or considered entering a clinical trial (n=237) (see Table 2). Of those, nearly three quarters (72%) chose a treatment trial, and 20% entered a symptom management trial. Sixty-five percent agreed to have their blood used in future research; however, 20% did not know if they had given permission to have their blood used in future research. 

Table 2. Clinical trial participation and treatment.			

				Asked to name the person who most influenced their decision regarding trial participation, physicians were cited by 57% of respondents, followed by unspecified others (18%), friends or family (14%), and other cancer survivors (10%).

Respondents were asked to list all the ways they had learned about clinical trials (see Table 2). Forty percent of cancer survivors listed a physician as their source of knowledge, and 14% cited other health care personnel. Combined, physicians and other health care personnel were most often cited by respondents (54%) as the way they learned about clinical trials. 

The Internet was used by 31% of respondents who searched for a trial, and 16% who used a listserv, news list or chat room. Interestingly, other unspecified individuals (17%) and family or friends (13%) were cited as sources of information about trials more often than either cancer information services (8%) or print media, such as journals and newspapers (4%). 

The survey's findings highlight the growing use of the Internet for cancer information. Of those who joined or considered joining a clinical trial, 31% learned about them on the Internet. 

Nevertheless, despite the popularity of the Internet, the findings of the study support earlier research

  that identifies the physician as central to clinical trial accrual. In this study, the physician was a primary source of knowledge about clinical trials overall (40%) and exerted the most influence on the decision to enter a cancer clinical trial for the total sample (53%). 

In addition, the findings suggest that clinical trial awareness education is needed within cancer centers for both potential trial participants and health care professionals, including referral sites and clinical staff. Examples include incorporating trial information into cancer center initiatives such as patient navigator programs and creating both generic and specific information for referral sites and clinical staff. 

Survivors were asked to identify the options available to them other than clinical trial participation (see Table 2). Most reported that the current standard of care (72%) was an option, and 15% had the option of another clinical trial. The choices "no other option" and "alternative therapy" were each cited by 13% of respondents. Most survivors did not seek a second opinion (67%) about entering the trial, and most believed they understood their disease and the clinical trial extremely well (54%) or moderately well (32%). Treatment options were most often discussed with the physician (94%), other cancer survivors (74%), and family members (70%). 

Respondents' expectations from a clinical trial included helping future cancer patients (60%), obtaining the best treatment available (42%), and extending survival while hoping for new therapies (41%). Forty percent considered participating in a clinical trial to obtain the latest therapy, 36% considered a trial to reduce tumor size or slow the spread of cancer, and 35% considered entering a trial to be treated by an expert in the field. The hope for a cure (25%), palliative care (22%), and cancer prevention (11%) were less frequently cited by survey respondents as reasons for clinical trial participation. 

Attempts were made to identify demographic characteristics associated with clinical trial participation. Table 3 provides trial participation rates by various demographic characteristics. Lymphoma (65.2%), kidney/bladder cancer (64%), and ovarian (60%) cancer diagnoses were significantly associated with trial participation (p<0.0001). Further, having a cancer recurrence (46.7%, p<0.001) and being male (39%, p<0.02) were also significantly associated with trial participation. 

Table 3. Characteristics of respondents associated with clinical trial participation.			

This project aimed to identify factors associated with clinical trial participation among a wide range of cancer survivors. Factors significantly associated with participation included: 					

Having a cancer diagnosis of lymphoma, kidney/bladder cancer or ovarian cancer.

The cancers associated with greater participation have a poor prognosis and are less common than other cancers. 

Reports indicate that only 3% of new breast cancer patients and less than 2% of colorectal cancer patients participated in clinical trials in the United States in 1990.

  Breast and colorectal cancer are more common than lymphoma, kidney/bladder cancer, and ovarian cancer and tend to have a better prognosis. The association of cancer recurrence and trial participation suggests that when standard care fails, physicians often look to clinical trials for treatment options. 

As mentioned earlier, the finding that a sample of predominately educated, computer literate cancer survivors most often learned about a clinical trial from their physician suggests that public education about cancer clinical trials is essential to improving enrollment in studies. Cancer centers carry the responsibility to incorporate patient education about clinical trials throughout their entire enterprise, to expand patient education beyond the physician to nursing and support personnel, and to support physicians who want to enroll patients in clinical trials. In this way, clinical trial participation may increase among cancer patients with primary cancer diagnoses and more common forms of the disease. 

Navigator programs within clinical cancer centers can be designed with a clinical trial education component and can offer an institutionalized system to inform cancer patients about clinical trial options available to them. General nursing and support staff indirectly involved in clinical trial research can be identified and trained to educate newly diagnosed cancer patients about potential clinical trials and encourage them to address the option with their physician. 

This study had several limitations. Technical problems with the online survey resulted in lost data, particularly with responses such as "other" and "specify." Further, the online survey did not require completion of one field before moving on to the next question, resulting in missing data for several questions. 

Finally, the study sample is predominately Caucasian, educated, and computer literate. Thus, future research should focus on minority, less educated, and underserved cancer survivors and employ a variety of collection methods. 

This study was partially funded through a grant from the Coalition of Cancer Cooperative Groups. The author wishes to thank both the Coalition and the Cancer and Leukemia Group B, in particular, for their support of this project. 

To improve enrollment in oncology trials, one patient advocate group went straight to the source.

A Survey of Survivors

"I don't want to be [given a lot of bull] by CROs, so I need to know myself what's at the heart of clinical trials." This uncompromising statement from a top executive in a flourishing young European biotech company should provoke some reflection within the clinical trials community. 

The author of the remark was Andre Hoekema, the senior vice president of corporate development at the Belgian company Galapagos, during a presentation of his company to journalists in June. Hoekema is no novice. He has 20 years of biotech experience, including as managing director or business development director of Invitrogen, Molecular Probes, and Crucell, and research and project management at DSM Life Sciences, MOGEN, and Genentech. He is the inventor of over 20 series of patent applications, resulting in 15 patents issued in the United States. So, he already knows a thing or two. 

Galapagos is no bubble, either. It has a market capitalization of around €190 million ($250 million), a cash position of over €50 million, 450 employees, and has raised nearly €90 million in private placements and share offers since it was created in 1999. It has a portfolio of promising drug discoveries, a revenue-generating range of pharma services, and a strategic alliance with GSK in osteoarthritis. And in 2007, it expects revenues to top €55 million and to double last year's R&D investment to reach €33 million. 

So what's behind Hoekema's combination of skepticism and curiosity about clinical trials? 

The circumstantial reason is that the company now has a product on the threshold of Phase IIb: oestradiol glucoside, developed for treatment of menopausal symptoms. Out of an extensive pipeline ranging from rheumatoid arthritis to cachexia, and from osteoarthritis to bone metastasis and osteoporosis, this is the first time the company has progressed itself to the end of Phase IIa. Although the company strategy so far has been to develop its products through to clinical proof of concept, it now wants to take a product further to provide it with experience that it believes will be valuable in planning development of its upcoming bone and joint disease candidates. "We've never designed trials," admits Hoekema. In his view, "The biggest problem is patient accrual...and we need to get our feet wet in that area." 

That explains the need for information. It doesn't, however, explain the reserved attitude toward contract research organizations (CROs). That can come only from a deep-rooted suspicion—or at the very least from a perception—that, to put it slightly more politely than Hoekema, not all CROs are always entirely reliable or credible. 

This should give pause for thought to CROs. Rightly or wrongly, justifiably or not, the impression is current among senior and serious players in significant and growing companies that some CROs are not delivering what their potential customers expect, and are even trading on the credulity or gullibility of inexperienced clients. 

If Galapagos was the only company likely to be looking for CRO services in the near future, the matter might hardly merit comment. But it isn't. Belgium isn't the biggest country in Europe or the most fertile in drug development. But even this pint-sized state boasts a wealth of up-and-coming drug firms with product pipelines stretching increasingly into clinical trials—and is therefore in the market for CRO services. 

Belgium has only 2% of the European Union's population and less than 1% of its area, but it has 100 biotech companies together employing over 8304 biotech employees, spending €500 million in biotech R&D, and generating an estimated €3.2 billion in biotech-related revenues. These companies are embedded in an innovative pharma industry that has a headcount of almost 30,000 employees. 

In Flanders alone, which is more or less the northern half of Belgium, focused discovery-and-development pharma companies have been raking in venture capital funding for their early development programs: At the top of the range, Ablynx, with its program of antibodies targeting oncology and immune diseases. The company raised €40 million last year. Actogenix raised €20 million for its therapeutic programs targeting gastrointestinal diseases, auto-immunity, allergy, and metabolic diseases. 

There were plenty of other signs of health, too: Tigenix raised €14.5 million to back its work in regenerative medicine, joint surface repair, adult stem cells, and targeted therapeutics. Pronota obtained the same sum for its protein biomarkers. And in early 2007, Movetis—a spin-out from Janssen Pharmaceutica—raised €49 million. 

One of the key attractions for venture capital investors in Flemish companies is the exit opportunity via initial public offerings. In contrast to many other countries, Flanders sees multiple successful biotech IPOs and, equally as important, significant value increases post IPO. 

Increasingly, these companies are bringing their projects through to clinical trials. During June, Movetis, which specializes in developing compounds for gastrointestinal disorders, announced the start of a Phase IIa multiple-dose trial with one of its lead products, M0002, an orally-active selective vasopressin antagonist that inhibits water re-absorption from the kidneys. Although it is only six months old, Movetis already has a portfolio of four clinical and four preclinical compounds, and proclaims its intention of bringing innovative therapeutics to the market for the treatment of gastrointestinal disorders. 

There is a perceptible dynamic toward growth and expansion in the region. TiGenix announced in June that it was acquiring a cell expansion facility from Cell Genesys of Memphis, Tennessee, to manufacture ChondroCelect, its lead product for cartilage repair, for the North American markets and to allow it to start comparability testing of the product as a prerequisite for a U.S. regulatory filing, anticipated in 2008. The product has successfully completed a randomized Phase III clinical trial and will be launched in Europe and/or in the United States in due course. 

A May update from ThromboGenics of its preclinical development portfolio revealed renewed focus on its advanced preclinical programs, notably on TB-403 (anti-P1GF—a humanized monoclonal antibody that blocks the formation of new blood vessels in solid tumors, reducing the growth and spread of cancer cells). Toxicology studies are well advanced and the product is expected to proceed to Phase I clinical trials by the end of this year. 

At the same time, PlGF, a vascular growth factor for the treatment of heart failure, is moving through preclinical evaluation and route of manufacture, with toxicology studies expected by the year end. Anti-VPAC, a humanized monoclonal antibody that increases the number of blood platelets after bone marrow suppression with chemotherapy, is currently under test in experimental animal models, and should move into toxicology studies by 2008. 

Following its successful February private placement of €31 million, DevGen says that progress in its pharmaceutical programs is on track, and it has ample resources to bring them toward clinical candidates and collaborations with pharmaceutical companies. Its diabetes program has also identified targets for rheumatoid arthritis and inflammatory bowel disease, and several models of inflammation are to be investigated further in 2007. In its cardiac arrhythmia program, additional efficacy studies are planned this year on compounds that have performed well in cellular and in vivo disease and safety models, with the aim of developing a chronically administered oral compound for the treatment of atrial fibrillation. 

What is true of Belgium is true, to a greater or lesser extent, across Europe: Numerous new biopharmaceutical companies with promising early-stage development and portfolios are moving toward the point where they need clinical trials expertise. At present, few of these companies have that expertise—and they are looking for it. So, who's out there to answer their call without any bull? 

Meanwhile, June saw the European Union devote further attention to personalized drug therapy. Germany, in the rotating chair of the EU until mid-2007, organized an expert meeting on "New Opportunities for Patients" in a bid to define the scope and limits of current drug innovation. Opening the meeting, Dr. Klaus Theo Schröder, state secretary at the German Federal Ministry of Health, set the tone with his remarks that personalized pharmacotherapy not only aims to tailor medicines to individual patients and groups of patients—thus increasing the effectiveness and safety of drug therapy—but that "this therapeutic approach is meant to contribute toward the more effective use of resources in the health care system." 

The agenda was as political as it was scientific. As the German Presidency made plain at the outset, "new knowledge in diagnostics and treatment in the field of genetics, as well as developments in biotechnology, will have an impact on the national health systems. Moreover, the success—and hence the future position—of the European pharmaceutical industry vitally depends on how European companies and research centers working in this field are able to position and establish themselves in the face of international competition." 

The conference acknowledged that pharmaceutical innovation is hugely dependent on uniform regulation and authorization of pharmaceutical products within the EU, and on guaranteeing and optimizing the accessibility of the newest and best pharmaceutical products for all patients. At the same time, it recognized that member states' ethical principles had to be respected in every aspect of pharmaceutical research and production. 

The penalties of ill-designed trials were, incidentally, demonstrated recently by the European Medicines Agency's rejection of a marketing authorization request for Amgen's Vectibix infusion for metastatic carcinoma of the colon or rectum. The application was for Vectibix to be used on its own after failure of treatment with a combination of anticancer medicines including 5-fluorouracil, irinotecan, and oxaliplatin. The active substance in Vectibix, panitumumab, has been designed to bind to the epidermal growth factor receptor, which can be found on the surface of certain tumor cells. 

The supporting documentation covered one main study involving 463 patients, where the effects of Vectibix in addition to best supportive care were compared with best supportive care alone. The main measure of effectiveness was the time before the disease started to get worse or the patient died. The patients receiving best supportive care alone had the option to start receiving Vectibix once their disease had started to get worse. 

The major concerns that led the Agency's experts to recommend the refusal of the marketing authorization were insufficient evidence to show a benefit of Vectibix, due to the way the main study was designed. In the first few weeks of the study, many of the patients originally receiving best supportive care alone started to receive Vectibix after their disease had got worse, making it difficult to compare the effects of Vectibix and best supportive care alone. In addition, Vectibix only had a very small effect in increasing the time until the disease got worse or the patient died, in comparison with best supportive care. Studies also showed that patients receiving Vectibix had increases in side effects. The judgement therefore was that the benefits did not outweigh the risks. 

 is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium. 

View from Brussels

New to the trials scene, many up-and-coming European firms are seeking the expertise of CROs they can trust.

Will the Real CRO Please Stand Up

Based on recent interactions with pharmaceutical, biotechnology, and CRO companies, it appears that the role of the clinical research associate (CRA) is undergoing intense examination and revision, driven largely by the adoption of e-clinical technologies and new study conduct practices. Several companies have noted the transition of their CRAs into data managers with an increasing amount of their administrative activities handled by electronic technology solutions. But mounting study conduct performance pressures during the past five to seven years are also pushing CRAs to redefine their roles all together: from monitor and taskmaster to trainer, helpdesk, and active site collaborator and motivator. Communication, e-technology savvy, and interpersonal skills have never been more critical to CRA effectiveness. 

Companies' expectations of CRAs have changed in several tangible ways. Standard operating procedures (SOPs) today, for example, tend to give CRAs less time to visit and to follow up with investigative sites. SOPs also require more detailed documentation of monitoring activities, including more elaborate enumeration of items contained in study binders. 

"CRAs across the board have been working longer hours than they did before 9/11, largely as a result of increased airport security," added Lorry Witte, RN, BA, CCRA, CCRC, a Twin Cities, MN-based study monitor. "Yet the pressure to beat deadlines is as tight as it has ever been, requiring CRAs to spend more time working on laptops in airplanes and in hotels and airports." 

Heavy travel burdens, rising airline-related costs, and delays have prompted many companies to decentralize CRA functions, including creating regional CRA positions and limiting travel within specific territories. "Regional CRAs, on average, spend 60% to 80% of their time traveling. But many now stay in the same time zone, so there are less connection issues and it's quicker and easier to get where they need to go," explained Sandra O'Donnell, MA, MT (ASCP), CCRA, senior regional CRA for ZARS Pharma. 

New regional positions can significantly reduce overhead costs. According to CRA managers in several major pharmaceutical companies, a large percentage of regional CRAs operate out of home offices. Doing so means, however, that CRAs need to be even more computer-savvy than their office-based counterparts because the bulk of communications and training happens electronically. It also means telephone and e-mail messages have to be more skillfully composed and delivered to prevent miscommunication. 

On the regulatory front, CRAs need to be prepared for more comprehensive tracking of protocol deviations and adverse events observed in new source documentation formats. "Clinical trial teams must decide upfront and agree with health authorities on what constitutes source documentation on studies involving remote data transfer, machines with memory, and patient reported outcomes," said Giovanni Della Cioppa, head of methodology and innovation in development at Novartis. "It's not always clear. But if it is not obvious and if the clinical teams don't spell it out, CRAs will each have their own view or they may not be prepared to track and report properly," he said. 

Without a doubt, CRAs today need to be a lot savvier about information technology than most veteran study monitors ever anticipated. They also need to embrace more regular and formal means of communicating with study coordinators and investigators rather than through sticky notes and memos. "It has been a tough—and dramatic—transition for many paper loving CRAs," said Laurie A. Halloran, BSN, MS, CCRA, a Boston-based clinical trial consultant. "I have seen monitors who could only monitor if they printed out the entire electronic case report form [eCRF] on paper. But those days are pretty much gone at this point." 

"Most CRAs, once they've done one trial using electronic data capture (EDC) never want to go back to paper. But study coordinators can be fiercely resistant, especially clinic nurses who aren't dedicated to research," said Minnesota-based CRA Witte. "To overcome the inertia, CRAs need to be contagiously enthusiastic about EDC. They also need to be proficient at using a variety of technology solutions if they are to champion speed-enhancing technology and troubleshoot with study coordinators," she said. 

"Electronically-based source documentation is a huge driver of change for study monitors," said senior regional CRA O'Donnell. "We see many sites still habitually printing out all source documents because they don't know how to set the security level on the electronic medical records (EMRs) to limit data access only to what monitors actually need to see," O'Donnell said. "For privacy reasons alone, study staff may not be able to accommodate techno-phobic CRAs by printing out patient records much longer." 

"CRAs not only have to have technological expertise but they must be more solutions oriented in their application of the technologies," said Halloran. "This is especially true when it comes to the problem of subject recruitment. It is no longer enough for study monitors to merely ask for enrollment head count. CRAs need to understand what attracts volunteers to a particular site or study. CRAs need to identify and to quickly react to participation barriers, such as transportation and the study visit schedule, which they often can do something about," she said. 

Looking ahead, it's likely that CRAs will have to meet certain minimum qualifications to be a study monitor—be it certification or licensure. Many sponsor and CRO companies, at the moment, remain unconvinced that passing a certification exam means a study monitor is better qualified and thus deserving of higher pay. "Even the Association of Clinical Research Professionals (ACRP), the leading CRA certifier, is still trying to define what the minimum education and training requirements for study monitors ought to be," said Halloran. 

Apparently, many CRAs are responding by seeking additional qualification from academic programs and advanced certification designations. "Certified CRAs go back for 24 credit hours of new learning every two years to retain their designation," said Witte. "But many are also looking to add new areas of qualification in study methods, for example, drug metabolism and regulatory, to set themselves apart." 

"And this training is imperative because, ideally, CRAs are passing on some of that knowledge at every site visit," added Witte. "Monitoring has evolved into more of a collaborative effort with study coordinators and investigators to get the job done better. Increased regulatory scrutiny has demanded that those encounters happen more frequently." 

"Increased use of technology, coupled with new clinical trial models, will eventually compel a new role definition for CRAs that includes greater IT knowledge and patient contact," predicted Novartis's Della Cioppa. "More and more, data will be transferred directly from the patient to the study database via portable devices and mobile phone technology. In terms of emphasis, CRAs in the future will move from raw data to the infrastructure that generates that data, including portable and patient-worn devices. They will need to ensure those devices are in order, those that break down are replaced, quality control is done, and that individual patients know how to use them." 

There is wide consensus that the study monitor community will be populated with fewer but more productive, indispensable, and—presumably—better paid CRAs. They'll be the ones forging more effective relationships with investigative sites, setting the speed and tone at which a myriad of technologies and solutions are adopted during study conduct—arguably the most critical juncture in the drug development process. 

"Given how far the CRA role has evolved to become more of a communicator and facilitator, CRA certification and training will need to distinguish between operational and scientific proficiency," added Della Cioppa. "But pharmaceutical companies can't do it all. I foresee the creation of a full university degree." 

Demand for experienced CRAs continues to grow. Pharmaceutical and biotechnology companies are relying more heavily on their study monitors to address high levels of study conduct inefficiency, particularly among their North American and Western European investigative sites. Adding helpdesk and new communication and collaboration skills to their portfolio of responsibilities, CRAs hold the key to unlocking marked improvements in investigative site performance."  

		Kenneth A. Getz MS, MBA, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: 		

Clinical Trial Insights

Today's CRAs must redefine their roles in the face of changing industry expectations and new technologies.

CRA: Jack of All Trades

The Pediatric Regulation has been born after a gestation period lasting some seven years. The objective of the regulation is to stimulate pediatric clinical research, which is still in its infancy in terms of defining the best usage of everyday medications for children. This article discusses some aspects of the Regulation and the hopes that it will bring pediatric research successfully to adulthood. 

The Regulation on Medicinal Products for Pediatric Use (Regulation (EC) No 1901/2006) entered into force in the EU on January 26, 2007,

  and will be adopted by each of the 27 EU member states. 

This Regulation aims to improve health among children in Europe by stimulating the development of new medicines for use in the pediatric population, ensuring that they are appropriately tested and authorized, and improving the availability of information about the use of these medicines.

The Task Force in Europe for Drug Development for the Young (TEDDY), established in 2005 and involving 18 partners from 11 countries, is expected to contribute significantly to the success of the Regulation since it too has the aim of promoting the availability of safe and effective medicines for children. 

Many medicines prescribed for children are given "off-label." In hospital pediatric wards, this figure is approximately 45% and in neonatal intensive care units it is over 90%.

  This off-label use is not always published nor adopted in Best Practice guidelines. 

Since there has been generally a lack of clinical research in children, they may be exposed to unnecessarily high risks, not in the least by being dosed ineffectively or by being given harmful doses of medicines. Children and adolescents represent a significant portion of the European population, about 25%. These are vulnerable patient groups with developmental, physiological, and psychological differences from adults; therefore, the need for adequate clinical research is evident. 

Several factors have contributed to the pediatric knowledge gap, including: 					

Extrapolation of adult dosing to children ("small adults")

Ethical concerns for exposing a child to undue risk in clinical studies

Smaller study populations and rare diseases

Logistical and technical challenges in conducting clinical trials in children

Lack of accepted clinical endpoints and validated pediatric assessment tools 

Lower marketing potential compared to adult medicines.

The most important reason for the lack of spontaneous basic academic or industry-led research is the practice of extrapolating the use of medicines used in adult indications and formulations to children on the basis of body weight. 

Clinical studies will be performed in accordance with the Clinical Trial Directive

One of the greatest hurdles in the clinical research of medicines in children has been issues relating to the ethical conduct of studies—particularly consent and assent. A "Considerations" document is in consultation currently, aiming to give guidance for the appropriate ethical environment for studying the pediatric population.

  Recruitment of children in clinical studies is a challenge since populations may be smaller and consent may be problematic. Obtaining consent from parents when their child may be very ill requires special diligence and care. They must be provided adequate information and time to make informed decisions about the risk and benefits of a particular study. There are also questions as to the validity of parental consent obtained under the stress of dealing with their child's illness. 

 Table 1. The FDA receives requests for pediatric studies from pharmaceutical companies as well as the agency itself and grants written requests based on clinical need.			

It should also be recognized that children have a developing capacity to give assent (or consent) and should be consulted if possible on their participation in a clinical study. Information should be presented in an age-specific manner, perhaps using formats such as magazines/comics/pictures. If a child refuses participation in the study and is considered capable of making that judgement, that should be respected. 

Retention of study participants is important since patients may need long-term follow-up for safety reasons, and the nurse practitioner/parent relationship is recognized as the most critical to successful patient recruitment and retention. 

Because regulatory agencies will require long-term data to be able to assess potential effects on growth and development, it is conceivable that ethical committees and insurers themselves will demand stricter insurance requirements including long-term liability cover. 

Pediatric studies require special design considerations. Placebo control can be used in short-term situations, provided rescue therapy is provided for and is more acceptable if alternative treatment is unavailable. 

Consideration needs to be given to invasiveness, conducting tests not within normal clinical practice. The limited blood volume, especially in babies and very small children, makes the conduct of Phase I studies particularly challenging and the use of pharmacokinetic and pharmacodynamic modeling techniques using data from adults and population pharmacokinetics may offer solutions. 

Many diseases relevant to the pediatric population are rare or infrequent. Design strategies to reduce patient numbers may include innovative study designs such as adaptive designs, cross over designs, and Bayesian analyses. Stratification may also be required to adjust for age, weight, and height and may additionally complicate study design. 

Studying a medicine as adjunctive therapy is a common method of demonstrating the potential efficacy of a new compound without denying the patient access to current gold standards. Subsequent studies may then confirm efficacy as monotherapy. 

Objective measures of efficacy may be difficult to apply in children. Objective measures such as death are fortunately rare, so surrogate markers of efficacy have to be found. Moreover, the competency of children to use techniques in taking medication in diseases such as asthma may affect the homogeneity of the data collected (e.g., peak flow readings, ability to inhale medication) and, therefore, efficacy measures. 

Age specific measures of endpoints, such as pain, need to be developed. Common techniques in children over the age of six years include assigning poker chips and smiling/frowning faces. Quality of life is often an important outcome, but scales need to be sufficiently child centered or family focused. They are often inadequately validated in children or tested for responsiveness to change. 

Children may not be able to communicate adverse effects satisfactorily. A medicine may also have long-term effects on growth and development, creating the need for continued pharmacovigilance and careful data mining to pick up signals for concerns. Adequate risk management plans are required. 

The European Medicines Agency (EMEA) through the Committee for Medicinal Products for Human Use (CHMP) has produced a guideline on the conduct of pharmacovigilance for medicines used by the pediatric population, highlighting the need to involve as many interested parties as possible.

The Regulation is similar to the Pediatric Exclusivity offered by the Food and Drug Administration (FDA) in the United States, where the Best Medicines for Children Act 2002

  and the Pediatric Research Equity Act 2003

  have been in force to increase pediatric drug information.

 A request to conduct pediatric studies may be made by the FDA or a pharmaceutical company. The request is granted based on the clinical need; if the data generated by the studies satisfies the FDA, then patent exclusivity will be granted for six months on all forms of the medicine with a patent. 

As of September 2006, 480 requests for pediatric studies had been received by the FDA with 326 written requests issued by the FDA either as approval of a request from a manufacturer or from the FDA itself.

  This represents a significant increase in the number of pediatric studies conducted. Additional labeling information on the safety, efficacy, dosing, and unique risks in children has been included on 100 drugs, and more than 250 pediatric studies of 125 products have been conducted. 

The Pediatric Exclusivity provision is due to sunset in Fall 2007, and it is not known whether FDA will continue to provide rewards after that time. The period of exclusivity has already been reduced to three months for products whose yearly sales exceed $1 billion. Reauthorization of the laws is strongly supported by the American Academy of Pediatricians.

The final Regulation is not significantly different than that published in draft form in 2004.

  Essentially, the Regulation requires that for any new medicinal product in Europe (including new indication, pharmaceutical form or route of administration for an existing authorized product), a Pediatric Investigational Plan (PiP) must be drawn up and submitted to the EMEA. The Regulation was formulated with the input of the Pediatric Expert Group (PEG), which is also conducting an inventory of the unmet therapeutic needs of children in various disease areas. 

This month, the PEG is being replaced by a Pediatric Committee (PC), which is a new committee of scientific experts in the EMEA that will be operational within six months of the Regulation coming into force. The committee will comprise representatives from the CHMP, representatives of the 27 member states, health care professionals, and patient associations. 

The primary responsibilities of the PC will be the assessment and agreement of PiPs, the evaluation of requests for waivers, and granting deferrals. The PC will also continue to identify the unmet clinical needs of the pediatric population. 

The EMEA recommends that the PiP should be formulated after the completion of the adult pharmacokinetic studies in order to stimulate early dialogue with the PC. This may be too early for some medicines where additional safety and efficacy studies in the adult population may be advisable before premature or unwarranted trials in children are conducted. 

If the product has a Supplementary Protection Certificate (SPC), the execution of a PiP will be rewarded with a six-month extension of the patent, provided data is incorporated into the Summary of Product Characteristics (SmPC). Authorization is required in all member states for this extension. 

This incentive is not considered adequate by European Pharmaceutical companies represented by the European Federation of Pharmaceutical Industries and Associations (EFPIA). They see the six-month period as the absolute minimum and would prefer longer protection to recoup costs.

  Conversely, generic companies would like a shorter period of patent protection.

The reward requires significant studies to be presented in the application dossier. Studies that were completed previously are not eligible for a reward but will be taken into account for the PiP. Additional rewards, such as tax allowances, may be provided by individual member states. 

New regulation provides the EU with a solid framework to stimulate R&D for children's medicines.

Pediatric Policies Grow Up

Major changes in clinical trial operations over recent decades require a whole new approach to human subject research, according to FDA officials, research organizations, and study sponsors. 

The current clinical research system is "extremely inefficient and therefore expensive," commented FDA Deputy Commissioner and Chief Medical Officer Janet Woodcock. Research is overburdened by regulations, often fails to ask the most relevant clinical questions, and thus produces quality data only at a very high cost, she said at a Drug Information Association (DIA) workshop on "Defining and Implementing Quality in Clinical Investigations." The workshop took place in Washington in May to launch a broad effort to modernize clinical research practices and policies. 

Just as Woodcock has spearheaded the FDA initiative to modernize policies for ensuring the quality of drug manufacturing and production, she and her colleagues want to apply quality risk management approaches to clinical research operations. A year ago (June 2006), Woodcock announced the FDA Human Subject Protection/Bioresearch Monitoring (HSP/BIMO) initiative to re-evaluate agency policies for regulating and inspecting clinical trials. The agency now seeks a more comprehensive re-evaluation of its policy and framework for clinical trial oversight as part of the Critical Path Initiative to modernize the scientific process for medical product development. 

Today's costly research system prompts sponsors to conduct more studies overseas and discourages scientists and clinicians from entering the clinical research field, reported workshop participants from industry and academia. The growing number of foreign trials makes it even more difficult for resource-strapped FDA to inspect clinical sites. While fraud is rare, said Woodcock, when it is discovered, "it tarnishes the reputation of the research enterprise and erodes public trust." Such events make it even more difficult to attract patients to enter clinical trials, further adding to the complexity and cost of drug development. 

FDA's response is to establish a Quality System for clinical research. Quality data, Woodcock said, should be sufficiently accurate to support FDA regulatory decisions, sponsor claims about a product, and treatment choices by physicians and patients. While absolutely perfect information is not realistic in a system with multiple parties and many sources of variation, a quality approach should be able to achieve an "acceptable control of variation" in clinical data, Woodcock explained. 

This involves setting standards for conducting trials and collecting data; utilizing risk-based approaches to define acceptable levels of variation in results; automating data collection and transmission; adopting new methods for evaluating sites and investigator procedures; and updating regulations and guidances for all these areas. As with drug manufacturing, quality clinical research means building quality into research operations instead of relying on later oversight and inspections to verify data quality. 

High-quality programs needed to protect subjects, improve data, harmonize global trials, and manage costs.

Applied Clinical Trials-07-01-2007

Reach Out to the People

A Survey of Survivors

Will the Real CRO Please Stand Up

CRA: Jack of All Trades

Pediatric Policies Grow Up

FDA Moves to Update Research Enterprise

Recruitment Done Right

eShowcase: iTrial EDC

eShowcase: VISTA