Web-based tracking and reporting tool removes the guesswork from trial management 

 (Chantilly, VA) has introduced Global Trials Manager (GTM) for anyone who has been involved with a study that could have ended months earlier if only they had known the direction the results would ultimately take. This Web-based application is designed to help life sciences companies better manage and shorten the life cycles of clinical trials.

GTM supports real-time tracking and reporting through a personalized site. This allows the processing of information to lead to faster decision making, improved project quality, and quicker time to market. From start-up activities to patient enrollment to the analysis of project metrics and results, GTM lets clinical trial professionals automatically respond to key data. 

With GTM, Northrop offers an integrated planning and monitoring environment encompassing all aspects of a clinical trial. The software platform allows for tracking of data and project management plans detailing monthly progress as well as patient details, patient procedures, and patient-reported adverse events.   

www.it.northropgrumman.com/clinicaltrialsIT

Meet the rigors of today's adverse event-reporting demands with a scalable, start-to-finish solution 

 (Stamford, CT) offers a suite of applications designed to meet the drug safety, pharmacovigilance, and risk management needs of pharmaceutical, biotech, and medical device companies as well as CROs. TOTAL SAFETY™ is a comprehensive, scalable solution designed to improve adverse event reporting throughout a product's life cycle. This type of advanced IT solution is currently in great demand, as life science companies find themselves under intense scrutiny by the public, health care professionals, regulatory agencies, and regulators. 

The Web-based, user-friendly TOTAL SAFETY Suite includes: ARISg™, agXchange™, SafetyMart™, Safety Composer™, and ClinicalConnect™. All of the applications work in concert as a suite or can be used separately, depending on individual business needs. With the 21 CFR 11-compliant agXchange, TOTAL SAFETY™ enables life science companies to securely submit electronic documents with a thorough audit trail. 

Each of the suite's programs is designed to integrate with most of the industry's technology infrastructures.  

New authoring release frees up even more time to tackle the meat of regulatory submissions   

 (Wayne, PA) saw an opportunity to enhance its authoring product with some added features. The company has released a new version of its StartingPoint authoring software that takes away even more of the burden of document formatting, allowing authors to focus on the critical content of regulatory submissions. 

The StartingPoint 2.0 package contains nearly 200 authoring templates spanning all five CTD modules, test scripts for clients to use when validating StartingPoint within their environments, a comprehensive user guide, and a style guide. 

StartingPoint 2.0 features support for auto-numbered heading styles and quick-access buttons for commonly used tasks like adding captions, cross-references, and additional symbols. Also, Octagon has added a toolbar button to this version of StartingPoint that keeps unsupported or error-prone styles from corrupting the document.  

Octagon Research Solutions, (610) 535-6500, 

Articles

eShowcase

EShowcase

Twenty years ago, when the research-based European pharmaceutical industry started to panic about the gathering tide of patent-expiry dates for many of its leading products, its anxieties were met in part. 

Some relief came from the creation of supplementary protection certificates—the consequence of the industry's energetic campaign for patent term restoration. But even more effective relief was provided by the growing trend toward innovation through biotechnology. This led to the development of new classes of highly sophisticated products that seemed less vulnerable to generic copying than the classical chemistry-based products that the industry had depended on for half a century. Not any more. 

The technological innovations that provided pioneers with new types of products are proving double-edged: generic nemesis is catching up, as the same technological innovations make it possible for competitors to exploit the same technology and produce copies—biosimilars, as biotech generics have come to be inelegantly termed. 

For the first time, many patents protecting first-generation biologic innovations have come to an end in Europe, making the creation of generic versions of these medicines technically possible. Against this background, 2006 promises to be the year of the battle of the biosimilars. And the clinical trial community is likely to be caught right in the middle of it. 

The European Medicines Agency in London (EMEA) has set up a working party on biosimilar medicinal products, and a glance at its work plan for the year tells its own story. It is holding four formal meetings of two days each, but the real work will be going on behind the scenes. It will be finalizing a new guideline on nonclinical and clinical issues in relation to biosimilar medicinal products containing biotechnology-derived proteins as active substance, on which consultation ended in late 2005. And it will be doing the same, and on the same timetable, for guidelines on similar biological medicinal products containing somatropin, recombinant erythropoietins, recombinant human insulin, and recombinant granulocyte-colony stimulating factor. 

Concept papers are also due to appear by April 2006 on nonclinical and clinical issues for biosimilars containing recombinant á-interferons, and on immunogenicity assessment of biological/biotechnology-derived proteins, with new draft guidelines on each subject being released for formal consultation before the end of the year. And the third quarter of 2006 also promises to see a three-month consultation start on an update to EMEA's note for guidance on non-clinical and clinical issues in relation to comparability of medicinal products containing biotechnology-derived proteins as active substance. Revision is needed, says the Agency, since comparability issues are now separated from development and evaluation of similar medicinal products. The working party will round off the year with a specific training course for regulatory staff and experts on assessment of similar biological medicinal products. 

EMEA had already been preparing its ground for what will be a difficult discussion. In particular, it organized a meeting in Paris at the end of 2005 with key biotech players, academics, and others with an interest. The responses to this meeting mark out clearly the terrain the battle of the biosimilars will be fought over. 

EuropaBio, one of the European associations defending the pioneers, welcomed the EMEA-initiated dialogue, but issued a firm call for the EU "to settle all outstanding important issues before the first biosimilars enter the market." It says that these issues need to be discussed "in a transparent manner in order to ensure that biosimilars will be used safely and effectively, including the need for a unique name and label for a biosimilar." Clear and distinct labelling is essential to avoid confusion between the innovator product and a biosimilar, and to facilitate pharmacovigilance obligations, EuropaBio explains. And the chairman of its healthcare council, Dr. Andrea Rappagliosi of Serono, emphasized the need for "sound and science-based guidelines." 

				The Emerging Biopharmaceutical Enterprises (EBE)—representing Europe's smaller pharmaceutical firms with an involvement in biotechnology—also welcomed the opportunity for discussions, with similar emphasis on "an open, transparent setting." And it claimed that the ultimate goal of the emerging framework of guidelines "should be to ensure biosimilar medicines do not compromise the safety of patients."	

It isn't very hard to decipher the code being employed by the pioneers in their formal statements. There is a common thread in their allusions to "balancing the state of our existing knowledge of these complex medicines with the need to increase access in a safe, legitimate manner," or to "appropriate risk management programs," "labelling that allows physicians to make informed decisions," and "appropriate pharmacovigilance and postmarketing surveillance." Basically, they don't want copy products slipping into the market through a back door—and they urge a clear and rigorous regulatory regime as the best way of stopping that from happening. 

EBE decided its statement should not leave anything open to doubt. "Biosimilar medicines are not generic products, and therefore require different development, assessment, and registration approaches that are adapted to their specific nature and complexity. Unlike traditional pharmaceuticals, biologic medicines are made through a process involving living cells and have the potential to cause serious immune responses if not manufactured, tested, and monitored properly," it insisted. And now that the EU is putting a "transparent and clear regulatory pathway" in place, "companies developing biosimilar medicines have a responsibility to follow this pathway and ensure that the products concerned demonstrate the standards of quality, safety, and efficacy expected by patients and prescribers." 

The companies that are pressing to get their biosimilars onto the market are—unsurprisingly—seeking to defuse all the concerns about safety and maximize their own unique selling proposition: They can give health care providers a better deal because their products are going to be cheaper. 

Greg Perry, director general of the European Generic Medicines Association (EGA), announced on the fringes of the Paris meeting: "The current level of biological science and recently enacted pharmaceutical legislation in Europe mean that the next generation of affordable medicines is no longer a distant dream, but rather a soon to be realized reality." He emphasized that Europe's biosimilar companies "have the scientific expertise and the technical experience to produce safe and effective follow-on pharmaceuticals based on medicines derived from biotechnology." 

Hitting where originator companies can provide little counter-argument, Perry also underlined that "Europe's health care systems are more than ready for the cost relief these new products will bring in addition to increased patient access to life enhancing treatments." EGA claims that the first wave of just six biosimilars is capable of generating savings of more than US$2 billion per year on Europe's overall medicines bill. "This amount would allow an additional 500,000 people suffering from kidney failure to receive EPO treatments, prolonging the time before they need dialysis," it argues. Similarly, EGA presented figures suggesting that biosimilars could offer savings of up to 40% on the seven biologicals in the top ten injectable medicines in Europe. 

				So while EGA talks about a "solid science-based agenda" too, its interpretation of solid science is ensuring "timely and efficient access to these more affordable biological products" by making them substitutable and interchangeable for originator products, and by applying "the established risk management framework pragmatically and sensibly."			

The territory where these two forces will clash—with pioneers seeking to mount their final stand against losing their market to dubious copies and copyists determined to win what they see as realistic evaluation of their products—is, of course, on clinical trials hill. Tough trial requirements and evaluation will provide a discreet mechanism for keeping copies off the market. As EBE says, its members "are confident that our regulators will take care to ensure the proposed clinical trial programs for biosimilar products do not put patients at risk." By the same token, generous—or what EGA calls "pragmatic"—interpretation of what is needed to prove a copy can do as much as the originator product will allow health care providers to cut their bills. 

Observant readers of this column will have noticed a reversion to the use of EMEA as the designation for the European Medicines Agency. It's not an accident—it's a tribute to a distinguished professional with a worldwide reputation in the clinical trials community.  

A casual remark in this column about the discrepancy between that name and initials of the recently renamed European Medicines Agency triggered a response from no lesser figure than the agency's Advisor on Integrated Quality Management, Marijke Korteweg. I had mischievously pondered in passing ("It's the Children Again," 

 October 2005) about when the agency would adopt initials that fit its new name and stop using its old acronym EMEA, derived from its working title: European Medicines Evaluation Agency. 

Marijke pointed out to me—with characteristic precision—that EMEA didn't accurately reflect the previous formal name either, which was originally the European Agency for the Evaluation of Medicinal Products. When the legal change in name to the more convenient European Medicines Agency was considered, serious investigation was conducted into changing the acronym, related to the domain names EMEA and EMA. But "the outcome was that EMEA should be kept," she told me, and pointed out with equal precision, "The actual logo, EMEA, always had that second 'e.'" 

If I were to be ungracious, I might still ponder about why on earth the agency ever chose EMEA in the first place, since the acronym never reflected its real name. But I shall instead draw my lesson from Marijke's accompanying comments, which firmly relegate reflections on the Agency's name to the margins of discussion. "I believe we should focus in the first place on the quality of the deliverable and the efficiency of our processes," she insists. "Some 399 staff in 20 languages try nowadays at the EMEA to do so, and I hope they can help to make health care in Eu-rope better. If we can contribute to a world-class regulatory system, it may satisfy more than one stakeholder." 

And Marijke is pushing ahead with her customary energy to help achieve just that. Plans are under discussion for an exercise in the benchmarking of medicines agencies right across Europe, based in part on the work undertaken by the EMEA in the last few years to help integrate new member states from eastern Europe into the EU's system of medicines regulation. Watch this space for further news. 

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

View from Brussels

As patents expire, clinical trials will be caught in the middle between copyists and original innovators.

Battle of Biosimilars

In their article, "Reducing Placebo Response: Triple Blinding & Setting Expectations," (

, November 2005), Kirby and coauthors identify factors that increase placebo response. Such factors decrease the efficacy of signal detection in placebo-controlled trials. Fewer than half of all registration trials for new antidepressants and anxiolytics between 1985 and 1999 separated drug from placebo, where placebo responses were often large.

  In their article, Kirby et al. focus on interactions between subjects and site personnel that can bias assessments and influence study outcomes by increasing placebo response. Nonspecific therapeutic effects of interactions with caring staff, bilateral expectation of benefit, functional unblinding of raters, and ratings inflation are recognized factors that contribute to placebo response rates. 

As remedies, Kirby et al. suggest the use of blinded raters and the provision of standardized instructions to subjects. They suggest that raters should not interact with subjects prior to or after the rating process and that raters should be blinded to study specifics, including randomization ratios and likely side effects of the investigational drug. They also advocate raters not be aware of study qualification criteria and that patient expectancies be managed during informed consent procedures and prior to each assessment. 

Factors contributing to elevated placebo response rates are widely recognized as methodological confounds that diminish signal detection efficacy in clinical trials.

  Evidence of rater inflation to qualify subjects for study participation is striking

  and grows as required severity increases. Rating inflation may be counterbalanced, in a pernicious way, when identification of subject response, defined by low scores, is required for participation in relapse prevention trials. Feltner et al. found evidence that the same raters who inflated scores to initially enroll subjects in a study also deflated scores at the end of open-label treatment to randomize apparent "responders" into the relapse prevention phase of the trial.

  Such inflation and deflation of rating scores likely reflects confirmation bias on the part of the raters, best defined by Yogi Berra as: "If I hadn't believed it, I wouldn't have seen it." 

The remedies proposed by Kirby et al. are theoretically attractive, but they face practical limitations. First, sites and investigators are paid for enrolling subjects, not for excluding them. Second, human raters are fundamentally limited in their ability to make reliable and unbiased assessments. Computer interviews are not subject to such limitations, providing procedurally consistent and reliable interactions with perfect repeatability. Computer assessments possess all the characteristics advocated by Kirby et al. 

Assessment fidelity is not aided by the inclusion of the warm fuzzy inconsistencies produced by subject–rater interaction. More than 30,000 Hamilton Depression Rating Scale assessments have been obtained by interactive voice response (IVR) technology that is accepted by the FDA as a primary efficacy measure for adult outpatient antidepressant registration trials. IVR assessments were also the primary efficacy measures that supported FDA approval of Lunesta. 

IVR uses touch-tone telephones to administer fully standardized interviews and scoring algorithms that cannot be influenced by treatment unblinding, both attractive attributes for clinical assessments. Convenience and constant availability make daily (or more frequent) assessment possible, an impractical goal for human rating procedures. Error checking of responses occurs at the time of data collection, and immediate storage to electronic files expedites subsequent analyses. Auditory interaction largely overcomes functional illiteracy, currently estimated to affect 22% of the U.S. population. Sensitive topics are disclosed more openly in nonhuman interviews. Subjects are familiar and comfortable with computer interactions over the telephone. 

IVR assessments are more convenient, reliable, and consistent than human raters, presenting instructions and information exactly as programmed at every assessment. Turnover, vacations, and variability of staff regarding training and experience make such consistency impossible for humans to achieve. IVR assessments also cost less than human assessments. 

Lest we worry this problem is unique to mental health or clinical trial raters, idealistic medicine residents were found to comply with self-defined practice "protocols" only 22% of the time. Given computer reminders of their own rules for practice, compliance improved to 51%, justifying McDonald's subtitle: "The Non-perfectability of Man."

Humans are wonderfully varied, creative, adaptive, idiosyncratic, and variable. These are admirable attributes for solving many problems in accordance with desires and expectations. Computers are repetitive and consistent, and reliably execute tasks as programmed. Computer auto-pilots actually perform better airplane landings than humans in low visibility. Computer interviews are more consistent and maintain structured interview techniques better than humans can. They cannot be influenced by factors outside the interview process. Repetitive clinical assessments in randomized clinical trials are not the forte of human raters, even when they're paid well for doing them. 

is a research scientist with Healthcare Technology Systems, Inc., 7617 Mineral Point Road, Suite 300, Madison, WI 53717, (608) 827-2440, fax (608) 827-2444, email: 

*To whom all correspondence should be sent.

1. A. Khan, S. Khan, W.A. Brown, "Are Placebo Controls Necessary to Test New Antidepressants and Anxiolytics?" 

International Journal of Neuro-psychopharmacology,

2. J.H. Greist, J.C. Mundt, K. Kobak, "Factors Contributing to Failed Trials of New Agents: Can Technology Prevent Some Problems?" 

3. D.J. DeBrota, M.A. Demitrack, R. Landin et al., "A Comparison Between Interactive Voice Response System-administered HAM-D and Clinician-administered HAM-D in Patients with Major Depressive Episode," NCDEU, Boca Raton, FL June 1–4, 1999. 

4. D.E. Feltner, K. Kobak, J. Crockatt et al., "Interactive Voice Response (IVR) for Patient Screening of Anxiety in a Clinical Drug Trial," NCDEU, Phoenix, AZ, May 28, 2001. 

5. C.J. McDonald, "Protocol-Based Computer Reminders, the Quality of Care and the Non-perfectability of Man," 

Guest Commentary

Authors comment on Kirby et al.'s remedies for placebo response.

Reducing Placebo Response?

We've all heard the promises. New data management systems will reduce the time required for clinical evaluation of drugs, resulting in faster, less expensive clinical trials. By eliminating the built-in inefficiencies in capturing and processing clinical trial data, it is said that pharmaceutical companies can slash some of the staggering costs associated with drug development today. 

If these promises were true, we would already have seen a significant improvement in the clinical trial process. After all, the typical pharmaceutical company uses a dozen different software systems to automate its work. Unfortunately, these specialized software packages have, for the most part, failed to live up to their promise; it can still take up to nine years and $600 million dollars to bring a drug to market. 

Part of the problem is that many of these systems are capable of handling only one discrete process in the complex course of a large-scale clinical trial. More significantly, the systems are not designed to integrate with other specialized clinical trial applications, despite the best efforts of industry groups promoting standards for data exchange. 

Because these standalone applications were not designed and built to share information, researchers spend valuable time re-entering the same data at each step in the clinical trial process. Such manual data re-entry is a recipe for introducing errors into trial results, requiring still more time to edit and correct the data. 

When the technologies don't work together, and there is no way to aggregate data across systems, then software becomes just another obstacle to completing a timely, affordable, and successful clinical trial. 

Industry groups have defined and published a variety of standards and definitions that enable data to be shared at different points in the development and distribution lifecycle of a drug. We are all familiar with the efforts of groups such as Health Level 7 (HL7) and the Clinical Data Interchange Standards Consortium (CDISC). 

Adopting these standards is an important step toward sharing data across the industry, but the standards themselves are not enough. They provide a framework for consistent data but do not enable pharmaceutical companies or organizations participating in clinical trials to actually move data in an automated way from one phase, application, or platform to another. 

In other words, adhering to standards can make data available in multiple contexts through a labor intensive process of data importing and exporting. But the next step, a critical one for data accuracy and process efficiency, is to develop seamless interoperability between systems so that data is automatically accessible and sharable across applications, platforms, and computer languages. To do that, the pharmaceutical industry requires systems that are based on shared technical standards and built with components that easily connect. 

In spring of 2005, our two companies, Broadpeak and DataLabs, joined forces to demonstrate the power of interoperability for improving trial processes. We set out to illustrate how separate systems from separate vendors can provide seamless support for clinical trial data when each system is built using industry standard technologies and an open architecture for interoperability. 

Broadpeak provides a site management package that helps pharmaceutical companies and contract research organizations (CROs) accelerate the recruitment, selection, and initiation of new sites for a clinical trial. Our portal software, Site Manager, integrates work at different locations and coordinates communication and collaboration among participants. 

DataLabs provides a data management system that streamlines the entire process of data collection and analysis, while also promoting greater data integrity. DataLabs Clinical™  enables those conducting clinical trials to enter data directly into a Web-based template in real-time, or to efficiently transcribe data from paper records, all based on a common platform. 

Although the value proposition of each product is compelling on its own, we recognized that what pharmaceutical companies really need is an interoperable solution that can integrate the entire process. After an introduction from our shared business partner, Microsoft, DataLabs and Broadpeak decided to work together to improve the overall process of managing data in a clinical trial. 

The resulting Clinical Trial Management System supports electronic data capture (EDC), paper data entry, and comprehensive data management. Using the combined capabilities of our two applications, a clinical trials manager can progress from managing investigator credentialing, patient enrollment rates, and reimbursement to viewing specific case report forms (CRFs) and patient information on an investigator-by-investigator basis. 

All the site, investigator, and logistical data are provided by Site Manager, while the clinical data comes from DataLabs' Clinical. But such distinctions are transparent to the user. The tight integration of the two software applications creates the connections automatically, behind the scenes. 

Because a standards-based open architecture is, by definition, nonproprietary, companies can choose technologies from many sources to achieve interoperable solutions. In the case of DataLabs and Broadpeak, the Microsoft stack of software provided assurances that our systems would integrate easily. 

Both DataLabs Clinical and Broadpeak Site Manager were built using Microsoft

  .NET technologies, the Microsoft framework for connecting systems and exchanging data. Each system uses CDISC-compliant XML for data exchange and a robust set of Web services to enable communication between applications and across platforms. 

In addition, Broadpeak built its secure online portal using Microsoft Windows

  Services. The portal, which is customized for clinical trial processes, provides a platform for managing data exchange with DataLabs' Clinical as well as with other openly architected systems. 

The combination of Web services and the SharePoint framework enabled our two organizations to integrate solutions quite easily. In a matter of 30 hours, developers had created a Web part out of the DataLabs software to plug into the collaboration workspace provided by Broadpeak. The technical people described it as a simple and straightforward mapping exercise. 

First, they exported all the CDISC XML data points from the DataLabs software using its existing Web services. Then they imported that information into the Broadpeak system using the same XML and Web services. The technologies used to build the products made the marriage between them easy. 

The success of the partnership between Broadpeak and Data-Labs is based on more than a common architecture. At its heart is a mutual desire to work toward the larger business needs of our customers, and a shared willingness to use open, accessible technology standards to deliver shared data. 

For the pharmaceutical industry, the advantages of such a partnership are clear. With an interoperable solution, companies can expedite data collection and aggregation and get a consolidated view of clinical trial status and results. By using systems that can pull data together from different levels, phases, and locations, trial decision-makers can access critical knowledge at a pace not previously possible. 

The strategic use of technology facilitates this kind of process improvement. DataLabs and Broadpeak were able to partner successfully because we use the same Microsoft technology stack and we believe in interoperability of systems. Because our technology is based on an open architecture, it is highly adaptive. With proprietary software, technology can be a barrier to change. But with a standards-based architecture supporting interoperability, technology becomes an enabler of process change. 

While the partnership between Broadpeak and Data-Labs worked quite well—so well, in fact, that DataLabs completed an acquisition of Broadpeak in November 2005—it has not been one effortless path forward for our companies. Merging technologies was relatively simple; educating customers about the value of interoperable systems has been far more difficult. 

Although pharmaceutical companies have great interest in digitizing their communications, their options up to this point have been limited to standalone solutions or, in some cases, hosted service offerings. That being the case, they often don't immediately perceive the value of an integrated approach. 

Addressing this problem will require greater cooperation among software vendors as well as a greater commitment to open standards. What the industry needs is a larger vision for how open standards can drive interoperability, and, by extension, make significant improvements across the clinical trial process. Ultimately, that's where the merger of Broadpeak and DataLabs provides its greatest value. It demonstrates that system interoperability is not only possible but also practical, and that the business advantages of standards-based interoperable systems include lower costs and faster time to market for the pharmaceutical companies that deploy them. 

Automating and integrating the clinical trial process can yield major competitive advantages. But the interoperability that companies, including Broadpeak, DataLabs, and Microsoft, envision for the pharmaceutical industry go far beyond joining data across clinical trials. For example, a portal that can integrate clinical trial data can also provide other data that an investigator might want to see, if that data is accessible in standards-based systems. In fact, the whole communication process between the sponsors, CROs, Institutional Review Boards (IRBs), investigators, and others involved in the trial process could be automated. 

Other systems could be integrated as well. The clinical trial stage, as complex as it is, is only one piece of the whole process of developing, approving, manufacturing, marketing, and delivering new products. Key pieces of data are reused—and re-entered into different applications—throughout the various stages. But a truly interoperable architecture could allow data to be entered only once and used appropriately at predetermined points. 

To move from vision to reality, however, pharmaceutical companies must deploy technology solutions that are based on an open architecture. Slowly, we are seeing the development of an ecosystem of companies that believe in open architecture and use Microsoft's .NET framework and Web services to build their applications. 

If the industry demands this kind of open, shared architecture from all vendors, no longer settling for proprietary stand-alone niche applications, then software companies will follow. Vendors that want to offer their customers the best services at the lowest cost will build to open standards and integrate their offerings with strategic partners to provide a higher level of integrated services.  

 is President of  DataLabs, Inc., University Research Park, 101 Academy, Suite 250, Irvine, CA 92617, (888) 773-0099, email: 

 is Vice President, Product Management ' Collaborative Solutions, DataLabs, Inc., 1180 Welsh Road, Suite 100, North Wales, PA 19454, (215) 631-7030, email: 

Notes from the Field

With the help of Microsoft, Broadpeak and DataLabs prove seamless integration is possible.

Realizing True Interoperability

The recent spate of adverse publicity surrounding Vioxx and other blockbuster drugs has intensified the U.S. Food and Drug Administration's scrutiny of novel therapeutics in the pipeline. While this reaction is understandable, it comes at an unfortunate time. The industry has been making great strides in moving toward a more streamlined approach for conducting clinical trials, with the goal of shortening the time to market for drugs and medical devices in development.

Public opinion notwithstanding, patient safety is of utmost concern to all parties involved in a clinical trial, as evidenced by the number of safety reviews conducted during any clinical program that are reported to an array of safety monitoring bodies, ranging from Institutional Review Boards to the FDA. Although the recent focus is on postapproval pharmacovigilance, enhancements in trial safety systems could improve the monitoring of a product's safety before the new treatment reaches the market. This achievement may rest on the shoulders of a new clinical trial methodology being made possible by Web-based electronic data capture (EDC): electronic safety alert messaging. 

The next evolutionary step in the safety process, automatic electronic messaging gives sponsors and other key personnel notification of potential adverse safety trends during ongoing studies. Notification can be pushed through any number of devices, ranging from cell phones and desktop PCs to PDAs and pagers. This form of immediacy in a clinical trial is further improved when it can be achieved through safety monitoring and messaging conducted in real-time—one of the key reasons for using a Web-based EDC system. 

Biopharmaceutical companies are historically slow to adopt new technology due to the complex regulatory and risk- adverse environment in which they operate. However, the pharmaceutical industry is now acknowledging the value of improved information technology solutions for clinical trials, which represent the most expensive phase of drug development. Industry analyst firm IDC issued a Life Sciences report last year stating that, "while the market for clinical trial management systems and EDC is still immature, it is expected to grow exponentially through 2008." It also pinpointed the areas of most concern to pharmaceutical and biotechnology companies when selecting an informational system. These concerns include the ability to track enrollment and study progress across multiple test sites, as well as functionality for identifying and managing potential study delays (including safety issues) before they become severe. It's no coincidence that these are also primary factors for selecting an EDC system. 

Today, sponsors understand that they can no longer afford to wait weeks or months to extract and compare data derived from clinical studies being conducted at multiple sites.  There are a number of products on the market that can streamline clinical trial data management. However, a Web-based methodology is best suited to provide the framework for the rapid assimilation of data across multiple sites and collapse it into an analyzable format that automatically generates safety alerts when pre-established safety thresholds are exceeded. 

Real-time automatic safety alerts have several human and financial advantages, including the following: 					

Patient safety is assessed on an ongoing basis and is not restricted to annual or biannual Data Safety Monitoring Board meetings.

Safety data between treatment groups can be analyzed by the EDC system without breaking the study blind; alerts do not reveal study data and are sent only to key personnel.

When multiple studies are stored in the same EDC system, safety data can be compared across all the studies.

Safety alert triggers can be specific to an adverse event  (e.g., myocardial infarction) or they can be more broadly defined (e.g., all cardiovascular events).

Minimization of patient risk, including early termination of a clinical trial when the data shows safety concerns.

Minimization of financial risk to the sponsor through the early detection of unsafe products; early detection allows the company to terminate a program and reassign resources to more promising candidates.

Potential to ease regulatory concerns for a clinical trial by providing an aggressive safety monitoring plan.

				There's no question that an automatic electronic safety notification process will save time, money, and potentially the lives of study participants in clinical trials. It may only be a matter of time before regulatory agencies require it to be part of the clinical trial process, adding further protection for the people who bravely participate in the research process.  

A Closing Thought

Today's technology makes significant improvements in trial safety systems possible.

Electronic Alerts Advance Safety

Global pharmaceutical and biotech sponsors spend an average of 6% of their clinical trial budgets on advertising and marketing to facilitate subject recruitment.

  In spite of this level of investment, 86% of these trials do not meet the enrollment expectations.

  Globally, more than 80% of trials fail to enroll on time, and the failure to recruit patients on time leads to loss of 85%–95% of days in a clinical trial.

  Hence, internationally, subject recruitment remains one of the main challenges for sponsors. As such, sponsors are seeking innovative solutions and to experiment with newer global territories such as India, which is perceived to meet the expectation of fast recruitment. 

The sheer presence of a huge potential clinical trial population makes India an attractive destination that has the potential for fast subject recruitment for western countries even without any overt advertisement and recruitment campaigns. This article attempts to analyze the geographic, socio-economic, cultural, and other India-specific market related environmental factors that may impact on subject recruitment and retention. 

Despite improvements, the health care system in India is still considered relatively unadvanced, and it is not supported by health insurance. Private medical support is very costly and is beyond the financial reach of the majority of the population. Thus, the majority of the population still remain largely dependent on government-run subsidized health care facilities (see Figure 1), even if these facilities are dispersed in diverse geographical locations. Hence, there tend to be many referral hospitals run by the Indian Government and trusts in major cities and towns that are specialized in certain therapeutic areas. 

These hospitals have gained popularity because of their subsidized nature, high quality, and advanced treatment options. Some of the names are well-known nationally in India, such as CMC (Christian Medical College, Vellore), Tata (Tata Memorial Hospital, Mumbai), and AIIMS (All India Institute of Medical Science, Delhi). Although these hospitals are located rather far away from major Indian cities, they attract a large pool of patients presenting with several diseases. 

 Figure 1. Total expenditure on health as percent of gross domestic product (2002 estimate).			

The public trust and medical college hospitals have found favor with clinical research organizations and pharmaceutical sponsors, as the investigators attached to these institutions are held in high regard for their experience and enthusiasm for clinical research. Furthermore, they have a large database of patients who are of a heterogeneous nature and profile. The institutions are also well-organized and have the appropriate infrastructure, facilities, and defined ethics committees to conduct trials that meet international standards.

By and large, these referral centers attract populations from diverse communities, with many of the subjects originating from geographically distant locations. Although these centers have the potential for very fast recruitment, because of large patient in-flows subject retention is an issue of concern. As the majority of clinical trial designs require continuous and long-term follow-up at different time intervals, there could be myriad tasks for the investigators and study coordinators to carry out to ensure compliance and follow-up and to reduce the chances of subjects being lost during follow-up. Considering that the subjects are drawn from distant locations for treatments, sponsors may have to agree on social admissions (e.g., planned hospitalization) and provide logistics, stays, and other support for those patients who are participating in a clinical trial. 

			USFDA's National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research highlighted the ethical principles and guidelines for the protection of human research subjects. In the context of this report, three basic principles (i.e., the principles of respect for persons, beneficence, and justice), among those generally accepted in Indian cultural tradition, are particularly relevant to the ethics of research involving human subjects. In contrast, it has been a taboo subject, and much discussion has focused on the idea that impoverishment, illiteracy, and social ills in Indian society may have an impact on the ethical conduct of a clinical trial. 

There has been a widely acknowledged belief that people with less education who are classed as impoverished cannot decide of their own free will and may, through socioeconomic compulsion, end up participating in a trial. But several observers argue against this belief, pointing out the danger of generalizations. The potential subject may be poor and illiterate, but this must not be mistaken for a lack of common sense or intelligence; they should be capable of making decisions on their own. They may not comprehend the complicated statistical design of a clinical trial, but if the investigator engages them through proper coaching and guidance, adequate information will be provided to the subjects. In this manner, potential subjects can understand, read, and comprehend in order to decide for themselves whether or not to participate in a trial. If they are not convinced, they will not participate. It must be remembered that these potential subjects have an equally strong commitment to their life and loved ones as the rich and more literate. Although it isn't very easy to convince them, it is also equally difficult to take them for granted just because they are on the lower social strata. If one reflects on this scenario, it is as equally or even more difficult to make a literate and rich subject participate in a trial. 

Impoverishment is considered by many to be another compelling factor for potential subjects in India to become involved in clinical trials. But if one looks into the existing health care system, the majority of the impoverished population, in any case, depend on free or subsidized treatment from government-run hospitals and dispensaries, since "health insurance for all" does not exist in India. So, participating in a clinical trial may be seen by these subjects as a means to ease some of their additional economic burdens in terms of medication and treatments. In a few studies, the trial design demands additional visits for tests and procedures; hence, the sponsor provides compensation toward the conveyance, stay, and loss of wages for the subject and other earning members of their family, as well as incidental expenses, which acts as a motivation and improves subject compliance and retention. Similarly, if the investigational product is temperature sensitive sometimes the sponsor may provide pool-refrigerators for use by the patients, either through a facility attached to the investigator's site or through their local physicians. These represent genuine compensation and logistical economic support for trial subjects, and would not be construed as an inducement or compulsion for enrollment. 

At first glance, some of these India-specific costs appear to be additional burdens to the sponsor considering India. However, these costs rarely represent a major expense and should be viewed with respect to the fast recruitment potential and the increased subject retention. It is a fact that poor and illiterate subjects are more compliant, as they are very sincere and follow protocol tests, instructed procedures, and advice from the physician. Hence, the so-called taboo of potential exploitation in developing countries because of illiteracy and poverty can be entirely ruled out with a positive shift in approach and orientation, and pharmaceutical sponsors should give equal justice and respect without any accusations of exploitation. Therefore, it is in every sponsor's interest to ensure that high ethical standards for clinical trials are maintained so there can be no accusations of subject exploitation. 

India is a country with diverse culture across the geographic territory. If one travels from north to south and east to west, several local dialects, subdialects, and life styles will be found. Not surprisingly, communication is achieved through more than one major language (see Table 1). 

Although the official language of India is Hindi as per the constitution and most people understand Hindi (barring a few states in the southern region), the English language continues to be used for all official purposes. The medium of education in India in higher studies (i.e., bachelors, masters, and doctoral programs) in science, medicine, pharmacy, nursing, and alternate medicines is in English. Hence, although culturally India is a Hindi-speaking community, because of the educational systems, the physicians, nurses, monitors, and most literate subjects speak, write, and understand English. Even India's judicial and governing institutions, health ministry, regulatory bodies, and ethics committee use English as the medium for day-to-day communication and management.

But it is a fact that many subjects are illiterate or limited, only able to read, write, and speak in their local language. Hence, looking at the multilingual culture, the sponsors and other clinical research stakeholders should make every effort to design information sheets in lucid local languages so that they are easily understood by the subjects and their relatives. What is important and essential in an Indian context is proper counselling and thorough guidance by the investigators, which may indirectly call for a lot of time spent mentoring the subjects—thus ensuring recruitment and retention. 

There are many other cultural factors that have major effects on patient recruitment and retention. Indians celebrate many festivals and cultural programs, and each community has their own set of cultural functions. Similarly, with poorer labor-class subjects, harvesting season is an important period during which time the family members jointly work together to earn a livelihood for the entire year. During festive and harvesting seasons, patient inflow to hospitals tends to be less, thereby leading to slower subject recruitment. Cultural programs sometimes even compel subjects to miss scheduled follow-up visits if the event falls during those days. Hence, knowledgeable investigators sometimes change the visit schedules, window periods, and drug-dispensing patterns depending on the cultural calendar of the subjects. Investigators also arrange for necessary staff, translators, study nurses, and other personnel who can understand subjects' cultural differences and languages in a trial context. 

There are other cultural values in the Indian family. For example, if a female subject participates in a trial, she gives her consent only after consultation with the male member of her family, who may be the father or husband. In this society, the male member takes charge of all decision-making processes. Another important sociocultural issue concerning unmarried female subjects is that they feel offended if they are asked to perform pregnancy tests, which is a common requirement in almost all protocols. Therefore, it is all the more important for the investigator to understand the cultural value of the society and educate both the subject and other leading member in their family for proper compliance.  

Another cultural factor in India is that subjects have deep respect for the study physicians. They listen to the study physicians and follow their instructions without any lapses. These cultural values help the study in terms of fast recruitment and better retention. However, this cultural factor also bestows a lot of responsibilities and demands on the physicians to behave appropriately without neglecting patient care and/or misusing patients' trust. 

In India, there are more than 30 strong networks/associations of physicians in different therapeutic areas. These associations are active and meet at frequent intervals at regional and national levels (see Table 2). Most of these associations have a Web site and publish their research articles in their association journals. The membership of each of these associations is in the range of 300–500 physicians. Hence, all the investigators associated in a clinical trial program interact to facilitate investigator and subject participation in a trial. 

Table 2. Potential Investigator, India			

However, physicians in referral and general hospitals who have an interest in clinical research have the dual responsibility of routine hospital care and clinical trial duties. The huge patient inflows in a typical hospital in India put considerable time pressure on physicians to see 200–300 patients during an average out-patient department (OPD) care period. Besides these OPD assignments, investigators attend other referral clinics inside the hospitals, which can be very fertile ground for screening for trial recruitment. 

Sometimes more eligible patients (availability) and less spare time (time-pressure) to complete the trial-related documentations, tests, and procedure formalities compel the investigators to recruit fewer subjects in a trial. In cases where there is a rare disease and inclusion and exclusion criteria are very stringent, the network and association of investigators can help identify the right subjects for a trial. With due respect to confidentiality, if the investigator discusses the trial synopsis with network members it improves the trial participation.

A frequent observation is that some Indian investigators do not consider subject recruitment a barrier at all and overlook the inclusion and exclusion criteria during the feasibility to predict an unattainable recruitment potential. But in practical terms, these investigators essentially fail to fulfill the commitment of recruitment. Hence, extra care should be taken to properly assess the recruitment potential during any feasibility studies. 

In today's scenario, India may not have more than 20 investigators in a major therapeutic area who are trained and experienced to conduct a key clinical trial. Lack of sufficient numbers of trained investigators and study staff may sometimes act as a strong barrier to recruitment in a clinical trial program, particularly if these investigators are occupied with competing trials. India's popularity as a location for clinical trials means that the chances of competing trials taking place are increasing. Hence, it is a must for industry sponsors and clinical research organizations to train investigators and include an additional number of sites and investigators in their clinical trial programs. This may necessitate the sponsors to provide financial and technical support to equip the site with trained investigators and adequate infrastructure and facilities. 

Over the years, Indian investigators, who have had the experience of participating in global trials, have realized the importance of their contribution in meeting the sponsors' recruitment needs. There has been an increase in expectations over the years in terms of fees, and some investigators have started expressing a desire to receive almost the same fees as investigators in western countries. 

Factors associated with clinical practice

Although clinical practice in India is more or less driven by western education, because of the heavy patient load, routine patients usually receive less attention and time from senior physicians compared with clinical trial subjects. In big referral hospitals, sometimes routine patients have to wait longer for treatment than their counterpart who elects to participate in a trial. Although the routine patients are given proper treatment, subjects are given special personalized care by the participating investigator and study staff. This acts as an indirect motivation for the subjects' recruitment and retention. 

As most of the clinical trial protocols are designed considering the criteria suitable for normal western populations, a consideration of ethnic factors for working in India is important. Similarly, there is a perceptible difference in stage and severity of disease at presentation in India from western counterparts, which makes it difficult to recruit patients with disease in early stages or with a mild to moderate severity. For example, most cancer patients on presentations are at advanced stage III/IV. So merely looking at the total number of patients with a particular disease would not provide accurate information when determining the recruitment potential. 

Many effective evidence-based treatments and practices are not performed in large numbers of Indian patients because of several socioeconomic factors. For example, the inclusion of a breast cancer patient who had previously failed on Herceptin (trastuzumab) therapy may be difficult because a large number of patients may not have received this treatment due to cost considerations, even though it may be considered to be an effective treatment. 

Another area of concern in recruitment and retention is the availability and wide spread practice of alternate medicines in India, such as homeopathy, ayurvedic, and unani.

  Many subjects may have taken these forms of treatment and would not have sufficient documentation of their treatment history. Thus, those patients may not be considered for recruitment in a clinical trial. In addition, if the clinical trial procedure in a subject's opinion is painful, time consuming, and yields no result, it is conceivable that few clinical trial subjects may migrate to these less costly alternate methods of treatment. 

Another issue of common concern is the nonavailability of sufficient hospital records and treatment histories for most of the subjects taking treatment in hospital OPDs. In the absence of a proper clinical history, it becomes difficult to identify potential subjects suitable for the trial. But looking at the current trends, many investigators have started creating  databases of potential subjects with chronic diseases, and over time this trend will facilitate the recruitment process. 

The Indian regulatory system allows recruitment of patients only after obtaining an approval for conduct of clinical trial and a test license for import of drugs from the Drugs Controller General of India. The process is fairly streamlined, and it takes almost 8–12 weeks to obtain the necessary regulatory approvals

  (see Figure 2). Unlike procedures followed in USFDA, a sponsor can start trial enrollment a month after sending in the application. 

Figure 2. An overview of the Indian regulatory approval process for clinical trials.			

In India, it is not possible to import a drug unless a test license is obtained. Therefore, subjects cannot be recruited unless written approval from the Drugs Controller General of India is obtained for the conduct of a clinical trial. Other procedures such as EC approvals from the individual institutional ethics committee and the finalization of financial contracts with the investigators do not take a long time and can be completed within that 8–12-week time period.

In the United States, it is not uncommon for patients to become interested in enrolling in a clinical trial without being briefed by their doctor. This is essentially because of the massive awareness created through recruitment campaigns and advertisements on Web sites and in other media. In India today, almost 100% of the subjects become enrolled through their doctors. Therefore, the most practical marketing efforts to expedite recruitment should include: 					

arranging regional meetings of the principal investigators and referring physicians

arranging focused clinics and treatment camps

providing leaflets containing inclusion criteria

Feature Article

Increasing cultural awareness is key to helping the country meet recruitment challenges.

Subject Recruitment: An Indian Perspective

Recruitment of investigators, research sites, and study participants is a constant concern during the course of any sponsored clinical trial. Before a study can even begin, pharmaceutical and CRO clinical research staff must strategically recruit clinical investigators and research sites. This time-consuming, intensive process is a critical first step for a study's ultimate success, but it is becoming more difficult in both the United States and Europe. An increasing number of studies now compete for resources as they seek targeted research subject populations. Fulfilling this need requires the participation of a larger number of centers in clinical trials across all areas of Europe and even in new territories around the world.

Photography: eyewire illustration: paul a. Belci			

Once investigators and clinical sites are established, subject recruitment and retention then ultimately determine whether clinical studies adhere to timelines. Although the European public is largely positive about participation in clinical trials, complaints by study subjects in European trials have risen sharply. Guided by the recent EU Clinical Trials Directive, CROs and successful, adaptive European pharmaceutical companies are addressing these issues in a proactive way. They are defining strategies for successful study subject and investigator recruitment, as well as study subject retention, to form a reliable base from which they can complete studies in a timely manner and to the highest quality standards.   

For the pharmaceutical industry, clinical drug testing and regulatory approval processes are more complex, more expensive, and more time-consuming than ever. Regulatory agencies—the gatekeepers of the marketplace for new drugs, devices, and therapies—increasingly require larger research subject populations for clinical trials.

  Agencies also require longer periods of treatment and observation before evaluating new drugs for safety and efficacy and, ultimately, approving them. 

In the United States, the average drug is tested on more than 4000 study subjects during 37 clinical trials before receiving FDA approval.

  In Europe, drug companies and CROs face similar trends toward tighter regulatory oversight and industry competition for study participants in increasingly large and complex drug development trials. 

Depending upon the size of the trial, the condition or disease being examined, and the participant population available, subject recruitment often proves to be a rate-limiting step for many clinical trials. Clinical trial project managers increasingly cite a relative paucity of study subjects for clinical trials worldwide as a major factor in delaying development times of new drugs or treatments in oncology and other therapeutic areas. Availability of study participants of course varies with therapeutic indication and target population. For example, although only about 2% of all cancer patients have ever participated in a clinical trial, some 80% to 90% of pediatric oncology patients are enrolled in studies.

For companies, any delay in approval for a successful drug can potentially cost millions in sales.  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 (

), an open resource for those interested in participating in clinical trials and for research professionals. 

Given that the stakes are so high for drug companies during clinical development, both U.S. and EU governmental regulatory agencies have focused a high degree of scrutiny on the clinical trial process out of concerns over perceived lax procedures, privacy issues, and conflicts of interest. A 2001 report by the Association of Clinical Research Professionals noted a tenfold increase in complaints against clinical test sites, a problem perhaps brought on by the changing landscape of clinical research in both Europe and the United States.

  Nonetheless, the general public seems to understand and support the value and promise of clinical research: A  European health survey conducted in 2004 indicated that two-thirds of the general population would be willing to participate in clinical trials.

Clinical studies are no longer exclusively centralized in teaching and research hospitals. Many clinical trials have been relocated to private practice or small clinical research centers under contract, often spread across the continent in pan-European trials. Companies are also implementing global clinical trials and mining databases in search of physicians who treat patients eligible for trials. Clinical research firms are increasing compensation to doctors as an incentive to actively recruit their eligible patient population. This compensation is at a similar level throughout the European region. Decentralization of clinical trials requires a greater degree of oversight by sponsor companies, more coordinated data management, and more standardized protocols for maintaining participants' privacy and rights.   

The most serious bottleneck in clinical trial recruitment comes in much larger Phase II and Phase III trials. In these trials, how participants perceive the potential benefits and risks of clinical trial participation influences their enrollment decisions. Successful recruiting centers typically use information on demographics, such as where a patient population is likely to be receiving medical care. Recruitment is also aided by utilizing information gained from feasibility studies, the experience of individual investigator sites and their subject database, the use of referral sites or primary care outreach activities, and knowledge of the clinical trial environment with respect to competitive studies.   

Other recruitment factors include issues in study design that may affect both enrollment and the ability to develop good, productive working relationships between the sponsors or their representatives and the clinical sites to optimize commitment and motivation to the study and recruitment of participants through the project team. 

Public opinion of clinical trials in Europe

The European public generally has a favorable view of clinical research. A 2004 survey found that 68% of Europeans would consider joining a clinical trial.

  Nearly two-thirds of those respondents were motivated "to advance medical science." Other most-cited reasons for participation included:  					

To obtain better treatment for their conditions (48%)

To obtain faster access to treatment for their conditions (34%).  

Patients are motivated to participate in clinical studies solely through the influence and encouragement of their treating physicians, particularly in Central and Eastern Europe. Based on the chance to participate in discovering a cure for a life-threatening, debilitating or degenerative illness, participation in clinical trials remains buoyant. 	

Table 1. Reasons for nonparticipation in clinical trials			

Despite the favorable view of clinical trials in Europe, a substantial percentage of eligible participants choose not to enroll in clinical trials. Table 1 lists some of the most frequently cited reasons for refusing to participate in an industry-sponsored oncology clinical trial.

  Although practical issues such as travel distance and expense play a role in subjects' refusal to participate, so do fears of placebo-group placement, the uncertain nature of experimentation, and a lack of faith or trust in medical investigators. 

However, when clinical trials are conducted efficiently with careful consideration for keeping participants comfortable, informed, and satisfied with their level of participation, subjects often report satisfaction with their contribution to clinical research. Table 2 lists responses from participants who have successfully completed oncology clinical trials.

Table 2. Positive experiences reported by patients in clinical trials			

Thus, study subjects need to understand what participation in clinical trials can potentially offer them. The following misconceptions should be addressed with a combination of investigator-driven education and a process that ensures protection of quality care and privacy during study participation: 					

Receipt of placebo—in some isolated regions in Central and Eastern Europe positive placebo responses are seen in many conditions simply due to intensified medical care. 

Lack of insurance (a problem largely confined to the United States).

Standard of care (improved in most clinical studies). 

Subject education: Recruitment or advertising?

Successful clinical studies pay special attention to educating potential study subjects, both in a general sense of how clinical trials work (education) and specifically how their clinical trial is designed, as well as what is hoped to be gained by their participation (informed consent). Subjects are also told of the risks and benefits, as well as the protection available for them regarding costs, privacy, and rights. In many countries in Europe, the adoption of the European Clinical Trial Directive (Directive 2001/20/EC of the European Parliament and of the Council of the European Union)

  and the European Data Privacy Directive 95/46/EC has increased the information required to be given to potential participants, and this can have a positive effect on enrollment in studies.  

In Europe, the shortage of clinical trial subjects, due mainly to competition, has forced drug and research companies to utilize proactive advertising, as well as participant and investigator incentives, to reach potential research subjects who are eligible for clinical drug testing. While the use of mass media outlets, such as radio and television, is not as widespread as in the United States, European companies are increasingly placing information about clinical studies on Internet-based trial registries, which allows patients and research volunteers to search for local clinical trial sites. As in the United States, these Web-based registries have become one of the most rapidly expanding ways to inform and recruit potential study participants. 

Some other strategies that have proved effective in the United States to meet clinical trial goals are being implemented in Europe. For example, patients in the United States are encouraged to be active partners in their care by seeking advice from patient organizations, as well as accessing information on clinical trial registries. Potential educational tools and strategies can include specialized publications that explain the goals of the clinical study and the requirements of participation. Such basic material can be augmented by information available on the Internet, from patient organizations, and through the general media. The use of the Internet as a source of information on diseases and clinical studies is increasing rapidly in Europe, as are the number of clinical trial databases.  

Europe is moving toward more intense patient contact through a variety of media.

Applied Clinical Trials-02-01-2006