In addition to preventing promising novel therapies from reaching future patients, clinical trial delays are estimated to cost companies $1.3 million per day, according to CenterWatch (www.centerwatch.org/), an open resource for those interested in participating in clinical trials and for research professionals.

ACT Magazine, February 1, 2006

Finding Subjects on the Internet
By Kenneth Getz, Dan McDonald, and David Heck

A top-twenty pharmaceutical company recently completed a pivotal trial of an investigational treatment for depression among 40 research centers. The company used a variety of recruitment methods including chart reviews, physician referral, newspaper, radio and the Internet. At the conclusion of the study, the sponsor determined that 16% of the 1,000 evaluable patients enrolled in the trial came from listing that trial on the Internet. The sponsor found that they had spent approximately $63.00 per enrolled patient through the Internet -- less than half their per patient spending for several other recruitment approaches implemented.

At the beginning of 2000, a sponsor found itself in a bind. A large, phase III rheumatoid arthritis study among 30 investigative sites had fallen several months behind its planned patient accrual rates. The sponsor decided to post its clinical trial online. In the first three months, participating sites reported receiving more than 2,000 e-mails and phone calls from patients responding to the Internet trial listing. A total of 80 patients were screened, and 20 enrolled. The sponsor determined that the costs to enroll patients through the Internet came to $95 per enrollee -- a cost-effective level relative to other approaches that were used.

In the past several years, the Internet has rapidly become a more prevalent and more viable patient recruitment resource. Although the incidence of Internet usage to recruit patients is relatively low at this time, clinical research professionals -- in sponsor and CRO companies as well as in investigative sites -- expect usage to increase dramatically over the next two years. For example, a survey conducted by the Association for Clinical Research Professionals (ACRP) in December 1999 found that less than 15% of professionals are routinely using the Internet to recruit patients. By 2001, however, almost half of survey respondents believe they will be regularly recruiting patients via the Internet. Similarly, in a survey conducted by CenterWatch among 61 sponsor and CRO companies, only one-third of companies used the Internet to recruit patients for at least one trial in 1997. Two-thirds of companies reported using the Internet for this purpose for at least one clinical trial in 1999.

The growing use of the Internet to recruit patients could not come at a better time. Presently, the pressure to commercialize new drugs quickly and cost-effectively is a primary operating objective for pharmaceutical and biotechnology companies. Yet patient recruitment remains a nagging and costly problem. Patient recruitment is already the largest cause of lost time during drug development, accounting for an estimated half of all delays that occur during study conduct. As much as 80% of clinical studies (phases I-III) are forced to extend the patient enrollment period beyond their initial contracted deadline . Presently, an estimated 4,300 patients are evaluated for a given NDA -- a 7% annual growth rate in the number of patients per new drug application .

Along with enrolling larger of patients per NDA annually, sponsor companies are also developing much larger numbers of new drug therapies. Whereas in 1994 there were an estimated 5,300 drugs in the R&D pipeline worldwide, in 1999 there were an estimated 7,100 drugs in the pipeline. The number of incremental new molecular entities (NMEs) has been growing annually by 6% for the past five years. Due to technology advances (e.g., genomics, combinatorial chemistry), the number of NMEs during the next five years are expected to grow by more than 10% annually.

Not only is it harder to find patient participants, it's getting harder to keep subjects in our clinical studies. Pharmaceutical and biotechnology companies are also pursuing more ambitious research projects today. These programs tend to be larger in scope with more trials and more data to collect per protocol. As a result, many clinical trials conducted today require a larger commitment (e.g., more visits, more procedures) from study subjects.

Presently, only an estimated 10 to 12% of the 50 million individuals in the US who suffer from chronic illnesses participate in clinical trials -- 90% of eligible patients are not entering clinical trials. There are numerous reasons for this low level of participation. Reasons ranging from poor protocol design (e.g., highly restrictive eligibility requirements) to negative public perceptions and patient distrust in health providers. Others argue that traditional approaches to reaching and informing potential study participants are failing due to changes in attitudes and behaviors that have occurred among both provider and patient communities. These traditional approaches include physician referral, chart reviews, walk-ins, investigative site initiated phone calls to patients, and study notices and bulletins in waiting rooms or common areas.

The Web and Patient Recruitment

The Internet now plays an active part in the lives of most North Americans. NUA Internet Surveys and Nielsen NetRatings report that an estimated 124 million people -- 45% of the US population -- are using the Internet regularly . And based on a recent survey, Jupiter Communication reports that 96% of all browsers use the Internet to routinely send and receive e-mail messages; 72% of users browse the Internet to research a topic; 51% use the Internet for daily news and stock quotes. Only 10% of browsers report that they regularly shop for products and services on the Internet.

In 1997, an estimated 26% of all browsers used the Internet to find health-related information. At the same time that the volume of browsers has increased exponentially, nearly half (47%) of all browsers now say that they use the Internet routinely to find health-related information. In response, more than 22,000 web sites have now been created to provide consumers and professionals with health and medical information.

Six years ago, only a handful of web sites were being used to assist patients in identifying clinical trials. These web sites were primarily listing services and they were largely funded by government agencies or health associations (e.g., the National Cancer Institute, National Institutes of Health, American Cancer Society, and National Aids Foundation).

Today, the structure of the Internet as a patient recruitment resource has divided into two distinct camps: (1) Content Providers and (2) Content Aggregators. Content providers tend to be neutral, independent parties -- government agencies, associations and publishing and information services companies. Content aggregators tend to be large health information destination web sites -- such as WebMD, Medscape, Onhealth. Aggregators typically license content from Providers in an effort to generate repeat traffic to their large web sites. These Content Aggregators -- such as WebMD -- are trying to offer content across a wide range of healthcare segments.

A recent slew of new, emerging Content Aggregators have sought to better 'monetize' the patient volunteer or study subject. These parties include AmericasDoctor.com (formerly Affiliated Research Centers), InterTrials.com, and DrugMonitor.com. The new Aggregators are focusing specifically on patient recruitment as one of only a few key service areas. They hope to offer web-enabled services to provide more comprehensive patient recruitment solutions including:

Clinical trial listings licensed from Content Providers

Online chat with a medical professional forums

Online questionnaires

Outbound and inbound e-mailing

Referral services to a network of investigative sites

Study volunteer compliance assistance

For more than six years, CenterWatch has been providing its Clinical Trials Listing Serviceä to patients and their advocates. The CenterWatch web site is one of the oldest and most comprehensive sites posting industry-sponsored clinical trials on the Internet. During the past several years, CenterWatch has been providing content to a large number of Content Aggregators including WebMD, DrKoop.com, Mediconsult, Medscape, AmericasDoctor.com and iVillage.

Based on our experience as a Content Provider, we have seen rapid growth in patient interest in learning about clinical trials and industry interest in using the Internet to complement other recruitment approaches. Almost all of the top sponsor and CRO companies in the United States have now used -- directly or indirectly -- our Internet service to recruit study participants. At any given time, an estimated 7,000 - 9,000 industry-sponsored clinical trials actively seeking study subjects are listed on the CenterWatch web site.

Since its inception, several thousand investigative sites and more than 350 sponsor and CRO companies have placed their trials directly on the CenterWatch web site. Investigative sites list their trials depending on their involvement in clinical research. A number of large academic medical centers and site management organizations list multiple trials. Many small investigative sites typically list no more than a handful of trials at any one time. In contrast, only 26% of sponsors and CROs post their individual trials on our web site. Almost three-out-of-four companies post multiple trials across a variety of therapeutic areas. The average study posted by a sponsor or CRO is relatively large -- an average of 19 geographically disbursed research centers -- and is placed on the Internet for almost a year.

As expected, not all trials are appropriate for Internet-based recruitment. Sponsors and CROs primarily use the CenterWatch listing service for longer-term chronic illnesses (98% of studies). Less than 2% of all posted trials are for acute illnesses. Still, we heard from a medical school resident who, in November of 1998, contacted an investigative site to enroll a patient who had presented in the emergency room with congestive heart failure. In addition, at this time a large percentage of trials are posted for those studies where recruitment is the most difficult. More than 40% of clinical studies posted by sponsors and CROs on the Internet are for cancer-related illnesses; 12% and 13% of posted trials are for endocrine disorders and infectious diseases respectively; and 9% of postings are for hematological illnesses.

Investigative sites are using the Internet to recruit patients across all clinical research phases. Sponsors and CROs are primarily using the Internet to recruit patients for phase II - IV projects. To date, almost half of all sponsor and CRO postings on our web site have been for phase III trials (43%); phase II trials comprised one-third of the total; and 19% of posted trials were for phase IV projects. We have recently seen significant growth in the number of phase IV programs listed by sponsor and CRO companies, and we expect this trend to continue. An estimated 275,000 to 350,000 people review the CenterWatch clinical trial listings every month. Much of this traffic is reached through our Content Aggregator affiliations. In March of 2000, for example, more than 330,000 people viewed our clinical trial listings. Based on an ongoing survey conducted on the CenterWatch web site, the majority -- 80% -- of all visitors are patients and their family and friends. Approximately 20% of all visitors are sponsors, CROs or health professionals.

Visitors to the CenterWatch web site are highly receptive to clinical trials. In a survey of almost 1,200 patients, 67% of those visiting our web site are interested in participating in clinical trials. Almost half of visitors to the CenterWatch web site have been recently diagnosed with an illness; one-out-of-four patients report that they are seeking an alternative therapy to one they are already taking; and 27% of visitors are family/friends of a patient who has been recently diagnosed.

Most patients who visit the CenterWatch web site (61%) do so once a month. Approximately 14% are visiting the site for the first time. And one-out-of-four visit on a weekly basis. The patient population visiting our web site appears to be a unique target audience. Only 23% of visitors to our web site have ever participated in a clinical trial suggesting that the Internet may prove a valuable means to reaching new study participants. In addition to visitor traffic, we now receive and respond to approximately 5,000 e-mail messages each month. Of this number, only 2 to 3% are e-mail messages from patients in Europe and Asia.

Approximately 31,000 people or organizations are now registered to receive notices from CenterWatch when a new trial is listed. Almost daily, CenterWatch sends out broadcast e-mail notices over the Internet to inform patients and advocates of newly posted trials. Many of these e-mail recipients, for example, are associations and patient support groups representing large numbers of patient members. Our broadcast notices over the Internet extend well beyond electronic boundaries. Numerous organizations including other publishers, support groups, and health educators print our notices in their literature and communications to their patient members. Combined with viewer traffic to our online listing of clinical trials, we estimate that as many as 500,000 patients and their advocates will see our clinical trial listings in electronic or print form every month.

Based on patient traffic logs taken in 1999, sponsors, CROs and investigative sites can expect an average of two to three patients per day to view individual trial descriptions for a diabetes or cardiology study. And one to two patients every other day will view a description of a trial in GI or urology. Sites posting various cancer or infectious diseases/immunology trials receive, on average, four visits each day to their trial descriptions.

At the present time, 36% of all patients and advocates viewing trial postings on our web site report contacting a research center. This is encouraging as it represents an increase of almost ten percentage points over the level of patient follow-up with the center two years ago. Of those patients failing to contact the investigative site: 44% felt they did not meet the eligibility requirements; 41% of patients were not in the appropriate geographic area; and 10% reported having trouble contacting the center. Less than 5% claimed it was due to a lack of interest in trial participation. This suggests that as greater traffic comes on to the Internet, and as a larger number of studies are posted, patient follow-up should increase.

In early 2000, the National Library of Medicine announced the introduction of a registry of government-sponsored clinical trials to begin to address the requirements of Section 113 of the Food and Drug Administration Act of 1997. This legislation calls for the National Institutes of Health (NLM), working with other agencies and companies, to coordinate the establishment of various databanks for public access to government- and industry-sponsored clinical trials information for serious and life-threatening illnesses.

As the largest provider of industry-sponsored clinical trial listings on the Internet, CenterWatch is positioned to assist industry in supporting Section 113 of the FDAMA mandate in much the same way that the NLM is assisting the NIH. However, there are several unique attributes of the CenterWatch listing service that are worth noting:

The CenterWatch service offers a unique level of flexibility and anonymity to the study sponsor. Our service lists individual clinical trials where patients are offered several ways -- telephone, mail, fax and e-mail -- to contact individual investigative sites directly. Most clinical trial listings on the CenterWatch web site provide concise summaries and encourage the patient to initiate contact and to establish a relationship with study staff. Companies are very receptive to our approach. We're seeing sponsors listing a wide range of clinical trials on our web site -- from life-threatening illnesses such as cancer and AIDS to migraines and acne. On any given day, for example, as many as 100 ongoing clinical trials are modified or added to our service. Our trial listing process is more natural for the patient with a lower likelihood of influencing patient self-selection and their expectations of study outcomes. The NLM registry and other government web sites, on the other hand, require the sponsor to provide a complete identification and detailed information about the protocol and eligibility criteria.

Information presented on the CenterWatch Clinical Trials Listing Service is managed closely by CenterWatch. We hold copyright on all of the listings that appear on our web site. As such, these listings are updated daily and cannot be duplicated or posted elsewhere. The CenterWatch service offers assurance to study sponsors and IRBs that clinical trials information can be updated, modified or removed at any time. And these changes will be reflected immediately throughout the Internet. CenterWatch licenses content to many of the nation's leading online healthcare portals, including WebMD, Medscape, Mediconsult, AmericasDoctor.com, Excite, and several others, for example. These relationships further extend the reach of our trial listings. The technical solution we have implemented with these health portals ensures that the trial information posted on their sites is kept up-to-date, and fully mirrors the information on the CenterWatch web site -- in real-time.

Information listed on the NLM registry -- or any government-sponsored web site -- is classified as public domain. Any organization or individual can duplicate public domain information without permission and without establishing a process for updating such data. Over time, it will become increasingly difficult for government-sponsored clinical trial listing services to maintain the quality and timeliness of its information.

As another quality control measure, even after protocols have been approved, study summary language for the CenterWatch web site is reviewed and approved by local and independent IRBs. This measure ensures more appropriate communication with the potential study volunteer. Since the NLM registry and NIH web sites are listing protocols, IRB approval of the protocol is all that is required.

Together, the NLM registry and the CenterWatch listing service complement each other to best support the FDAMA Section 113 mandate. CenterWatch is presently working to integrate its content with that of the NLM.

Intensification among Content Aggregators

Five years ago, there were but a few Content Aggregators looking to receive monetary compensation for patients enrolled in their client's clinical trials. Today there are an estimated 20 companies -- both large health portals and focused e-recruitment solutions companies.

Companies are pricing their services as follows: a small fee is collected for every patient that is screened for a clinical trial, and a larger fee for patients that enroll and complete a clinical trial. The fees typically ranged from $100 to $200 per enrolled patient. Historical and new entrant companies have reasoned that given the fact that companies pay $350 to $500 to recruit a patient on average, a $150 per enrollee fee is reasonable. The jury is out whether sponsors and CROs will pay these fees. According to DataEdge, pharmaceutical and CRO companies typically pay as much as $1,500 overall --combined recruitment, compensation and operating fees -- for an evaluable patient across all therapeutic areas.

DrugMonitor.com, which was founded in June 1999, launched a web site that provides an online screening questionnaire for potential clinical study participants as well as volunteer compliance assistance. HealthCare Integrated Services, Inc. announced the launch of CliniCure.com, a subsidiary that will provide web-based outreach for clinical research trials. Intertrials.com -- a start-up Internet company led by Leslie Michelson formerly from ProtoCare Trials (an SMO) -- announced that they had received $6 million in first-round venture capital funding to focus on Internet-based services that accelerate clinical trials. These services include patient recruitment and site selection.

The $60 million mid-January 2000 merger of AmericasDoctor.com and Affiliated Research Centers (ARC) has also caught industry's attention. This merger represents the first time a major health portal and a large centrally managed SMO have combined forces. ARC believes a key to the merger's success will be the ability to process patients through an established network of experienced clinical trial sites. AmericasDoctor is relying on its chat rooms, forums and its content to keep a steady stream of traffic coming to its site. Quintiles and WebMD are also developing services to recruit study subjects via the Internet though little has been announced along these lines at this time.

Focussed Content Aggregator companies offer a compelling new approach provided they are able to blend quality content with well-executed patient recruitment management. It is likely that Content Aggregators and Content Providers will form tighter alliances in the future in order to ensure that timely and accurate content is offered to the patients. This, in turn, will assist in generating and directing traffic to services designed to process and manage study subjects.

The distribution of clinical trials information over the Internet continues to evolve, making it an increasingly viable and valuable medium for reaching study subjects. With growing pressure on sponsors, CROs and sites to find, recruit and retain patients in their clinical trials, the Internet has quickly become an extremely important resource supplementing traditional approaches. The coming years will be very telling ones as the Internet evolves and matures

Applied Clinical Trials Supplement, June 2000