Skin is the largest organ of the human body, and its complex and sensitive nature toward various foreign and internal factors makes it highly susceptible to a number of diseases and disorders.  

The result of these foreign and internal factors (environmental, physical, microbial, hormonal, and others) is critical conditions and related symptoms.  

Pharmaceutical companies conduct clinical trials based on factors such as a promising therapeutic area, unmet needs for a particular indication, and the presence of a significant patient population. 

 The number of patients recruited for major indications from 2000 to 2010. 

Currently, there are many indications for which no appropriate treatment is available. Therefore, pharmaceutical companies are currently analyzing the potential of launching new therapies and tapping the potential market.  

An analysis of patients recruited for clinical trials which were "completed," "ongoing," and/or "started" during 2000–2010, showed that patient recruitment, among all the major indications under dermatology, was highest for acne vulgaris. 

GBI Research discovered that the highest number of patients were recruited for clinical trials for acne vulgaris, atopic dermatitis, candidiasis alopecia, and herpes zoster—the figure depicts the results. 

A study conducted on the number of patients recruited for clinical trials in dermatology shows that the total number of patients recruited for acne vulgaris clinical trials accounted for 48% of the total dermatology clinical trial recruitments, which accounted for a greater patient share than that of atopic dermatitis with 25%. The numbers of patients recruited for herpes zoster were 17%, followed by candidiasis with 9%, while alopecia clinical trial recruitment accounted for 1% of the total dermatology clinical recruitments. 

In the dermatology sector, most companies coordinate their research and development (R&D) activities to constantly expand their product pipeline with innovative drugs.  

Although there is a consistent and continuous threat from generics and other alternatives, companies in the dermatology therapy area are not reluctant to invest in R&D and are focused on offering new products to the market.  

In addition to the threat from generics, patient recruitment is another major challenge for clinical research organizations. Patient recruitment is the most time-consuming process involved in clinical trials. Recruitment of patients is more difficult than treating them. 

High competition is observed among the companies recruiting subjects with similar dermatological conditions. However, to achieve better results and easy determination of drug efficacy, the selection of subjects should be based upon the variability in dermatological symptoms/specification of the disease in patients.  

This can be achieved by following physician referral, advertisements, and by conducting patient awareness programs through seminars and other means.  

Adequate patient recruitment is necessary to ensure a successful trial within the scheduled time limit. Patient recruitment and enrollment within the proposed time limit enables the company to launch new products ahead of its competitors and maximize revenues from them.  

Following the ethical guidelines established by the relevant regulatory authorities is one of the more important requirements in avoiding external barriers to the progress of trials.  

— Syed Faiyaz Razvi is a Clinical Trials Analyst at GBI Research

Articles

News

Clinical Trial Recruitment in Dermatology

Choosing between placing a sizable bet on metrics to predict successful investigative site performance versus on implementing practices to support site performance success, most sponsors and CROs would choose the former. Ideally, both approaches play an important role. But most sponsors and CROs are investing in the former approach without much to show for it. Perhaps it's time that more sponsors and CROs focused attention on the latter? 

Under tighter budgets and timelines, a number of pharmaceutical and biotechnology companies and CROs have been analyzing reams of descriptive and historical performance data supplied by investigative sites and maintained in house to identify factors that better predict successful patient enrollment. Four factors have emerged as promising predictors: past performance, experience, investigative site focus, and historic speed to randomize the first study volunteer.  

Retrospective analyses conducted by Pfizer and Lilly, for example, suggest that investigative sites that have performed well on one study are more likely to perform well on subsequent studies. Lilly's analysis in particular has shown that a comparatively well performing site on one study has a 70% higher chance of performing better than typical sites on future studies. Lilly also found that poor performing sites on one study have a high likelihood of under-performing in subsequent studies.   

Investigator experience also appears to explain historical site success with some consistency. CROs and sponsors that have spent time analyzing site performance datasets have found that once a particular site has conducted six to 10 clinical trials, that site has a higher likelihood of meeting enrollment targets within the requisite time frame. Sponsors and CROs have concluded that investigative site operations move up a learning curve to achieve speed and effectiveness. 

Pennsylvania-based RapidTrials, in collaboration with a researcher at the Waltham, MA-based Heller School at Brandeis University, have found that investigative site focus and commitment to conducting clinical trials is associated with higher performance. Based on data provided by 50 pharmaceutical and biotechnology companies on 72 Phase II-IV multi-center protocols across 10 therapeutic areas, RapidTrials found that investigative sites with sufficient infrastructure and focus on clinical trials were 41% better enrollers than sites devoting their time to clinical practice with limited attention to clinical research.  

TTC, Inc. (also based in Pennsylvania), Merck, and Quintiles have each found that investigative sites quick to randomize their first patient tend to perform better overall. They argue that early enrolling sites know what they're doing. With a finite amount of time until data lock, early enrolling sites move through the contract and budget negotiations process faster, start enrolling patients sooner, and they leave more time to enroll patients throughout the study. 

Taken at face value, these predictive factors appear promising in their ability to assist sponsors and CROs in identifying and selecting top enrolling investigative sites. Past performance, site experience, focus, and early enrollment speed each make good common sense and, arguably, have been intuitive and anecdotal considerations utilized by study monitors and site selection managers for some time. Sadly however, operating conditions and real world sponsor and CRO site management practices are rendering these predictive factors obsolete before they've had a chance to be applied.  

The investigative site landscape, for example, is more fragmented today than ever. Of the approximately 23,000 FDA-regulated investigators conducting at least one clinical trial each year, only 35% are large, more experienced community-based sites and those affiliated with an academic health system; the majority are stand-alone sites conducting trials within a clinical practice. The investigative site landscape remains a cottage industry. 

A growing proportion of investigative sites are novices—new entrants in the clinical research enterprise. According to CenterWatch, in 2000 two-thirds of all active investigative sites reported that they had been participating in clinical research for more than three years. In 2010, only 56% of active investigative sites reported doing so. 

Turnover among this fragmented collection of investigative sites remains very high. CenterWatch has reported that four out of 10 US investigators on average, between 2000 and 2009, quit participating in clinical research each year up from 26% on average between 1990-1999. Investigative sites note that an onerous compliance burden, difficulties recruiting study volunteers, slow payment cycles, and the diminishing attractiveness of study grants have all contributed to the high drop out rate. 

Sponsors and CROs are increasing the number of countries where they conduct clinical trials each year. The globalization of clinical trials is in large part motivated by sponsor and CRO efforts to lower clinical trial costs by engaging sites that will accept lower study budgets while offering more rapid patient recruitment rates. The Tufts Center for the Study of Drug Development (Tufts CSDD) has shown that between 2002 and 2006, sponsors conducted their Phase II and III trials in 11 and 19 countries on average respectively. Between 2007 and 2010, sponsors conducted their Phase II and III trials in 18 and 34 countries on average. Many of the sites engaged in these emerging markets are newer and less experienced entrants in the clinical research enterprise. 

In an effort to diversify patient recruitment risk, sponsors and CROs have also been engaging larger numbers of investigative sites to enroll a smaller average number of study volunteers. This practice has forced companies to identify and select larger numbers of novice sites as many of the more experienced research centers cannot justify the high cost of committing resources and time to a study requiring only a few enrolled patients. 

The investigative site landscape is in a downward cycle, becoming ever more nascent and fragmented. Until it achieves scale and maturity, the site landscape will remain a moving target where metrics-predicted success will have limited value. Top performing sites will remain a scarce partner, trying to succeed in an operating environment that favors the lower cost alternative: larger numbers of less experienced investigative sites.  

Will this cycle be broken? Can we ever expect to see more predictable site performance? Several trends portend a period when the investigative site landscape will consolidate and mature. I've written about the growing adoption of integrated outsourcing relationships which may help drive the establishment of long-term preferred CRO-site partnerships to better assure higher levels of study conduct performance and efficiency. In addition, several relatively well capitalized international site management organizations have signaled their interest in acquiring top performing investigative sites. 

But predictable site performance need not only focus on the analysis of retrospective operating metrics. A growing body of research suggests that sponsors and CROs can positively affect site performance through improvements in protocol design; increased attention and support of site recruitment initiatives and operations management; and rising support of education and outreach initiatives.  

Eight years of research that my colleagues and I have conducted at Tufts CSDD on protocol design complexity suggests a major opportunity for sponsors to ensure study conduct speed and efficiency. Our research has shown that more complex protocols are associated with poor recruitment and retention rates, longer cycle times, and larger numbers of protocol amendments. In turn, each protocol amendment requires on average two months of time and a conservatively estimated $500,000 to implement. Streamlined and simplified protocols, designed with feasibility input from study coordinators and investigators, would dramatically and positively impact the performance of investigative sites. 

Quintiles recently reported success with the relationship managers it places in its select investigative sites. As part of its Prime Sites initiative, Quintiles found that a dedicated onsite manager keeps study staff focused and engaged in ensuring that select clinical trials receive the attention and resources required to meet timelines efficiently. A number of CROs have pointed to the importance of proactive investigative site support to ensure higher levels of successful performance. 

CISCRP and other organizations have routinely shown the positive impact of outreach and education initiatives on patient recruitment and retention rates. In one study conducted in 2003 for example, systematic outreach and education—particularly to minority communities—increased the number of patients inquiring about participating in clinical trials by 63%. In 2007, Lilly ran a public service announcement concurrently in select markets where it was also recruiting patients for pain studies. The public education campaign never ran immediately before or after a specific recruitment ad. Rather, it was presented independently, airing at different times of the day, but targeting the same demographic populations as that of the patient recruitment advertisements. 

Initially, Lilly found that investigative sites enrolled 38% more patients in markets where the public education message was airing concurrently. Over time, patients receiving the public education message showed a marked propensity to volunteer for Lilly's clinical trials. Eventually, enrollment rates per month doubled in those markets where the public education message aired concurrently.  

Higher levels of successful site performance are within reach for all sponsors and CROs. Eventually, metrics-based approaches to routinely and consistently identify top performing investigative sites may become more effective. Until then, the best predictors of site performance success require hands-on proactive support including—but not limited to—the design of executable and feasible protocols; attention and support of site operations and recruitment; and ongoing public education and outreach. 

, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, e-mail: 

Clinical Trial Insights

Research shows four factors best predict successful patient enrollment in clinical trials.

Predicting Successful Site Performance

(Münster, Germany) has expanded its Regulatory Affairs team with the addition of 

 (Durham, NC) has made several additions to its team including 

 as Vice President and Managing Director for the Product Development and Commercialization practice of Quintiles Consulting, and

, MD, as its Chief Medical and Scientific Officer. Spaeder succeeds 

, MD, who now leads the company's Phase I clinical research business. 

 as the Business Development Manager for the East Coast.

(Dublin, Ireland) announced the appointment of 

, PhD, to the position of President, ICON Development Solutions. 

to the position of Vice President, Human Resources. In this role, Sneff will be responsible for the global human resources function and staff in support of the company's strategic goals. 

 (Birmingham, AL) announced that pharmaceutical executive 

, PhD, has been named Vice President of the Drug Discovery Division. 

 has assumed the newly created position of Vice President of Operational Excellence.

 has been appointed Chief Executive Officer of 

(Warsaw, Poland) Chief Executive Officer where he will expand and oversee the entire North American operation.

, PhD, as Vice President, Bioanalytical Services, where he will provide leadership for PharmaNet's GLP-compliant bioanalytical laboratories in the United States and Canada.

, PhD, as the Director of Microbiology, and 

DO, as Vice President, Psychiatry–Scientific Affairs in its Therapeutic Expertise group.  

Leading the Clinical Trial Management services and supporting the company's business development team to advance Human Abuse Liability research, 

(Toronto, Canada) have formed a partnership to provide central IRB services. 

 (PRECOS) (Nottingham, UK) has signed a partnership agreement with 

(RCT) (Verbier, Switzerland) to provide scientific validation of existing data for cancer therapies. The partnership will see PRECOS provide drug efficacy work to support RCT's research on complementary medicines, so that evidence-based treatment choices can be made by patients and health professionals.

(West Bend, WI) have formed a strategic partnership agreement that allows both organizations to engage pharmaceutical clients strategically and accelerate first-in-human to proof-of-concept clinical development. 

 (Cranford, NJ) has formed a strategic alliance with the 

to provide its clients with access to enhanced assay development services. 

(New York, NY) as a preferred provider for full-service clinical pharmacology and exploratory clinical studies. 

 (Vancouver, WA), a clinical research and product development company, has deployed StudyManager Evolve software to manage its latest clinical study.

(Souderton, PA) Clinical Services business unit was presented with the ASQ Philadelphia Section Large Company Member of the Year award at the section's awards dinner held in Malvern, PA. The award is presented annually to a company with more than 200 employees with the leading participation in section activities.

(Research Triangle Park, NC) Executive Vice President 

through its Women in Business Awards program.

 (Minnetonka, MN) as one of the fastest-growing privately held companies in the United States by including the company on its "Inc. 5000" list for the fifth straight year.

 From left are Cathy Robinson, Tania Davis, Christine Gallagher, Susan Beattie, Jill Cooper, and Maire Mullin. Almac is carrying out genetic research to make advances in the field of personalized medicine.  

 (Craigavon, UK)switched up their usual workwear for jeans in honor of Jeans for Genes Day. By making a donation to the national charity, Jeans for Genes, staff helped to fund research into a wide range of genetic disorders which affect around one in 25 children born in the United Kingdom.

 (Norfolk, VA) has added quality oversight to its services for clients in the pharmaceutical, diagnostic, and medical device industries.

 (Manchester, UK) announced that its analytical laboratories in Livingston, Scotland, have successfully passed a GMP inspection by the US Food and Drug Administration without any "Form 483" citations. 

 (Lake Success, NY) research sites now have the opportunity to improve their patient stipend payments and manage their study budgets with a discount from Greenphire's ClinCard System. The ClinCard System enables sites and sponsors to deliver subject payments in a controlled and automated manner in compliance with industry regulation and in accordance with the specific requirements of each study.

 (Warsaw, Poland), an early clinical development services provider, announced the formation of MTZ-US Clinical Research in Massachusetts. This new office location in the Boston area will allow MTZ to better meet the needs of its customers throughout biotechnology hubs in the United States.

(Raleigh, NC) has announced the release of the third edition of respiratory care expert Jack Wanger's book, 

Pulmonary Function Testing: A Practical Approach

, recently published by Jones & Bartlett Learning in Sudbury, MA. 

 (Miami, FL) launched  their Latin America regional depot network with facilities in Mexico City and Buenos Aires.

 (Princeton, NJ) has expanded its drug metabolism services to include drug-transporter interactions with eight human transporters. Under this expansion, Covance now offers assessment of drug-transporter interactions involving major human transporters, key to drug disposition in a stably transfected, cell-based format.

 (New York, NY) has been selected to conduct a Phase I clinical trial of an investigational new drug for insomnia. The study will assess the safety, tolerability, pharmacokinetics, and pharmacodynamics in a group of healthy subjects and in otherwise healthy subjects who suffer from primary insomnia. 

 (Plymouth Meeting, PA) announced an open ePRO integration interface, which enables sponsors and CROs to integrate their own eClinical systems with CRF Health's ePRO platform, TrialMax®, to provide data collected from patients in real time to all study stakeholders.

(Greenwich, CT) announced an agreement for Catalent to acquire the Clinical Trial Supplies business of Aptuit LLC for cash consideration of $410 million on a cash and debt free basis. 

 (London, UK) has established a new legal entity in Israel. 

 has expanded with the relocation of its corporate headquarters to Miramar, FL. 

Business News

Industry news focusing on the people and organizations who work in the clinical trials profession.

Business and News Update November 2011

In June 2011, Pfizer announced the REMOTE trial, the first "virtual" randomized clinical trial under an IND to assess the safety and efficacy of Pfizer's Detrol LA, a treatment for overactive bladder.  

The study is specifically designed to test the methodology of the virtual trial concept, to determine if it can replicate the results of the previously completed Phase IV Detrol LA trial. The trial is called REMOTE for Research on Electronic Monitoring of OAB Treatment Experience.  

 we have written on the technology vendors involved in the trial—Mytrus, Exco InTouch, and Greenphire. Mytrus serves as the single coordinating center for patients, recruitment, the principal investigator, sub-investigator, and the coordinators; Exco InTouch provides the eDiary technology; and Greenphire is providing subject payments. 

The remaining technology piece comes from Perceptive Informatics, which according to Bill Byrom, Senior Director, Product Strategy at Perceptive Informatics, is providing the core clinical trial technology applications of Randomization and Trial Supply Management (RTSM) and EDC via IVRS. Perceptive's role is to support the trial and is working closely with Pfizer to serve as the central integration point to join all third party technology applications to present a seamless eClinical solution.  

 in an e-mail, "We are providing underlying foundational technologies to enable and power the patient and physician portal communities, as well as the integration and management of core eClinical solutions."			

How the technology fits into the trial: RTSM system controls the assignment of medication to patients and tracks direct-to-patient dispatch and receipt through integration with the patient-web interface delivered by Mytrus. This enables the single central investigator to manage effectively the direct-to-patient medication shipment and dispensing process. 

"We have integrated all third party data: central laboratory, ePRO (Exco InTouch), Mytrus for patient self-reported data, and telephone consultations data to enable our underlying EDC application to consolidate and report the full clinical data for each patient enrolled, providing remote monitoring and central management of all the data from the trial," Byrom elaborated.  

An advanced integration framework has enabled Perceptive to be the hub for all data integration between the clinical applications used in the trial. The solution provided by Perceptive offers a means for these technologies to work seamlessly and provide the work flow and data flow essential to implement Pfizer's new model for studies. 

According to Byrom, from a clinical trials standpoint, the REMOTE trial is a new paradigm in study execution that aims to eliminate the difficulties in patient recruitment by operating a study whereby patients from any location can enroll, independent of their proximity to a study site. The promise of this approach is to make clinical trials accessible to a much wider patient population and hence reduce the timeline required to enroll subjects.  

This kind of enrollment relies upon an effective means of identifying patients that may be eligible to participate outside of individual study site pools. Direct-to-patient advertising for clinical trial participation may be a key methodology accompanying this approach, and may also enhance the attraction of utilizing commercial trial participant databases which, until now, have had variable success due to the requirement to select only a subset of potential patients representing those within a short distance of defined study sites. 

He adds, "The study pushes the boundaries in the way trials are conducted—in particular the subject screening, consenting, medication dispensation, and safety management processes. It's a truly innovative concept that will have greater utility in future studies." 

Because the virtual trial approach represents a new level of automation and information exchange to meet the needs of patients, physicians, and clinical research teams, it provides a good example of Perceptive's commitment to technology innovation. "Our investment in our eClinical platform has enabled Perceptive to play the key role in providing the mechanism to integrate the combination of trial technologies in play to create a simple workflow for all key users: patients, investigator, and sponsor. The technology infrastructure and innovation Perceptive provides helps customers increase trial efficiency and improve data access," said Byrom.   

Perceptive Informatics is providing the core clinical trial technology applications to Pfizer's REMOTE trial.

Seamless eClinical Solution from Perceptive

The ethical aspects of biobank research have become a source of intense discussion after Swedish authors claimed that having to obtain informed consent for the use of left-over human tissue samples could be hampering essential studies. 

The requirement for informed consent for biobank research is problematic because it consumes resources that could be directed toward more research and/or healthcare, and it imposes a risk of selection bias, according to PhD student Joanna Stjernschantz Forsberg, and co-authors Professor Mats Hansson and Senior Lecturer Stefan Eriksson, PhD, from the Center for Research Ethics and Bioethics at Uppsala University. Clinical trials are being abandoned because informed consent is deemed too logistically difficult to obtain, they wrote in an online article published by the 

 Biobank research has a valuable role to play in R&D, but handling the consent process is rarely straightforward.( Source: Biotec Services International) 

"Well documented differences between individuals who consent to participating in biobank research and those who do not can threaten the validity of the results. If we, not unrealistically, assume that 70% of those contacted respond, and 5% to 10% of those who reply refuse consent, the missing data can obviously result in biased results," argued the authors. 

However, a blanket endorsement of consent-free research, even on biobank materials, seems unnecessary, noted Chris MacDonald, PhD, visiting scholar at the Clarkson Center for Business Ethics & Board Effectiveness, University of Toronto, Canada, in an e-mail response to 

 article. There are situations in which re-contact is impractical, or even dangerous, but not all cases are like that, and Canada's federal guidelines make this a case-by-case determination, for instance. In certain cases, subjects may not want their tissue used because they do not endorse the particular kind of research, and are ideologically/morally opposed to a study, he stressed. 

"It also has to be remembered that not all research—maybe very little—actually ends up contributing to the public good," he pointed out. "There's little reason to believe that the average tissue donor—or research participant, more generally—is in favor of whatever projects that the drug company sees as valuable. So in the case of corporate-sponsored research, the force of the 'common good' argument is severely diminished." 

In general, requiring informed consent for research on stored tissue samples and associated data helps safeguard the autonomy rights of donors, but Forsberg and her colleagues argue that this policy not only defeats the interest of society but also runs counter to the interests of the individuals it aims to protect. They think a way forward would be to adopt policies of broad, presumed, or no consent for research on leftover human tissue material, but they maintain that even the least controversial of these proposals—broad consent—has been criticized because it threatens patient autonomy. 

They noted that the time has now come for individuals to acknowledge that, in order to further their own interests, they must sometimes accept inclusion in common endeavors. "As individuals living together in a society, we limit our freedom in many ways in order to achieve common goals," they wrote. 

Patient material without having access to normal material from healthy volunteers as control is worthless, and the same standards should apply for patients and volunteers, commented another biotech specialist who wished to remain anonymous. Data is generated that belongs to an individual who might not be aware that he or she is bearing an illness or a risk factor which was previously unknown, and researchers must work out how to handle this challenge. 

Furthermore, there is some speculation that a group of senior German physicians intend to establish a kind of IT clinic, where all physical sampling of patient material and sampling of patient data will be compliant with the future bio banking regulations. 

Scandals such as the Tuskegee syphilis study and the retention of organs from children in the Alder Hey Children's Hospital, Liverpool, UK, have evoked much anger and contempt, according to Forsberg et al. To protect people from such offenses, extensive regulations have been put in place, and in some nations (e.g., Sweden and the United Kingdom), requiring informed consent has become the default position not only for invasive research but also for non-interventional research. Other countries, including Denmark and Belgium, permit presumed consent for such research. 

"Leftover material, stored tissue samples, and associated data can be used without consent, after approval by an ethics review board, because the minimal risk of harm is clearly outweighed for each individual by the increased chance of benefiting, directly or indirectly, from healthcare," stated the authors, whose research was supported by the EU 6th framework program AutoCure and by the Swedish Research Council through BBMRI.se.  

Securing specific consent can cause problems if researchers subsequently want to use the samples for a different study, and time and money may need to be spent on tracing the sources of the samples, perhaps many years after the material was excised, they wrote. In New Zealand, a planned study on the  prevalence of gene mutations for long QT syndrome was not done because informed consent was deemed "too logistically difficult" to obtain. In another study, the researchers attempted to obtain informed consent for research on surplus material from 495 renal transplant patients, and after a year the opinion of 26% of the patients had still not been ascertained, they noted. —

Global News

Biobank research has a valuable role to play in R&D, but handling the consent process is rarely straightforward.

Ethics of Biobank Research Come Under Scrutiny

There is a risk that the currency of terms like "innovation" will be devalued by over use in Europe. Hardly a week goes by without some new claim to have harnessed innovation to Europe's economic recovery, or to solving the problems of demographic change, or to building sustainable health systems. 

Amid so much hype and loose rhetoric, one organization at least has come a little closer to matching words with deeds. The grandly-titled Innovative Medicines Initiative (IMI) last month provided an overview of some of its achievements—and some of them merit recognition.  

This $2.4 billion program claims to be already generating "tangible results that will improve Europeans' quality of life," notably through better and safer medical treatment. It has been linking industry, academic teams, regulators, and patients' organizations in joint research and training projects. 

One of the consortia has created a tool to help understand diabetes and to test potential new drugs in laboratory conditions—an achievement recognized by the scientific community as a breakthrough in diabetes research. This IMIDIA consortium has generated cell lines that continue to live in the laboratory in test tubes and that closely resemble the beta-cells that malfunction in the human pancreas of patients with diabetes. The cell lines represent an invaluable new tool that was so far missing in diabetes research, allowing studies that otherwise would have to be done on fresh cells extracted from the human body. The current lack of understanding of the mechanisms of the failing insulin production and the death of the beta-cells in diabetes hampers the development of better treatments, and the new cell lines will be used to test potential new drugs against diabetes and to further unravel the causative mechanisms. 

Unsurprisingly, given the growing incidence of diabetes, there is more than one project studying the condition and its impacts. The SUMMIT consortium is developing methods to identify patients with a high risk of developing complications of diabetes, such as stroke or problems with the heart, kidneys, and eyes—complications that account for more than 10% of healthcare costs in Europe. Following extensive literature searches to identify changes in the body that predict such complications, researchers have identified a strategy for a new computer model to assist in prediction. They have also started studies with patients aiming to identify non-invasive markers of complications in the blood vessels. 

Another consortium has contributed to a better understanding of the mechanisms of chronic pain. The EUROPAIN project has revealed similarity between pain caused by chemotherapy and cold hypersensitivity. Scans have identified changes in the brain activity of patients with low back pain that can be used to predict pain intensity. Researchers have also identified several molecules in the body that could be potential new targets for the treatment of pain. 

Companies have pooled data to create the largest known database of studies on schizophrenia, including information on more than 23,000 patients from 67 studies in more than 25 countries, offering industry and academics unique opportunities for the development of tools and models that will help find targeted treatments for schizophrenia. This consortium has also assembled a database with data on 2,500 patients with major depression, which they are scanning for new clues to treat the disease in patients that do not respond to existing therapies and for predicting the response in those who do. Genetic analysis of DNA-samples of these patients has already identified targets for predicting the response to treatment and the limits of current predictions.  

Because more than seven million Europeans suffer from Alzheimer's disease and other forms of dementia, the PHARMA-COG consortium is developing methods to identify the most promising candidate drugs earlier in the development process. The researchers have proven that sleep deprivation induces cognitive impairment similar to that of patients with Alzheimer's disease in human volunteers, and have shown that commercially available drugs for Alzheimer's disease can reverse this cognitive impairment. This suggests that sleep deprivation could be used as a model of cognitive impairment to test the effectiveness of new candidate drugs.  

A major new study of severe asthma is being conducted by the U-BIOPRED consortium, which has recruited the first of over 1,000 subjects. Data related to blood, tissue, lung function, exhaled air, and the airways, plus reports of people's own experiences, will be used to build up a detailed picture of each individual's condition. By comparing data from hundreds of people, the team hopes to characterize different kinds of severe asthma, paving the way towards personalized treatments for patients—an undertaking that would be impossible for any research team on its own. The consortium has already produced an international consensus statement for the diagnosis and definition of severe asthma, which represents a key step towards the development of innovative patient-tailored therapies. 

Several of the projects will be useful across a broad range of development, by allowing the early elimination of non-viable potential treatments. A new computer model brings new accuracy to the prediction of whether a candidate drug is likely to cause serious heart problems in patients, and should help researchers pick up drug safety problems earlier on in the drug development process. The work of this eTOX consortium could reduce the wasted efforts in pursuing drug candidates that eventually fail because they turn out to be toxic to the heart.  

A consortium coyly rejoicing in the title of SAFE-T is developing biomarkers to similarly improve allocation of research resources to the most promising candidates. Given that fewer than 10% of all drug candidates tested on patients complete clinical development in current circumstances, because of potential drug safety issues, SAFE-T has evaluated and prioritized 153 potential biomarker candidates for tests with patients that could help predict drug-induced injury of the kidney, liver, and vascular system. A scientific strategy adopted by the consortium for the testing of biomarkers on patients' blood and other samples has been agreed with the European Medicines Agency and the US Food and Drug Administration. 

A project known as MARCAR has developed and proved the effectiveness of a method that helps identify chemical changes in the chromosomes that are related to non-genotoxic carcinogenesis. The detection of these epi-genetic changes can be used as early biomarkers to predict if drugs in development are likely to cause cancer.  

In parallel, a number of education and training projects are providing platforms for students and scientists that wish to develop their career in the area of drug discovery and development.  

IMI is funded jointly by the European Union (with more than $1 billion in cash) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) (with more than $1 billion of in-kind contributions). By sharing research results that have not been brought together previously, IMI project partners say they are building new methods, models, and tools that will speed up the development of novel therapies. A valuable side-effect of IMI is that it is also making Europe a more attractive place for private investment in innovation.  

As Magda Chlebus, Director of Science Policy at EFPIA, puts it, IMI is providing proof of concept for new public-private collaborations in pharmaceuticals. Using open collaboration to define and address common challenges, it offers a neutral platform for dialogue defining a common agenda and shared priorities for industry and academia.  

"IMI works," she told an audience in the European Parliament. "It is producing tangible deliverables after less than two years—a pace that no other funding scheme allows." In her view, "IMI connects the dots between science, health, and growth." 

Maria Vidal, a Senior European Union official responsible for medical research, insisted that research performed in IMI is based on a scientific agenda, prepared through consultation with all relevant parties, and focused on benefits to the patient. The research tools it develops can be rapidly and widely taken up within the scientific and industrial community, as a tailor-made intellectual property policy provides support. 

Mary Baker, President of the European Brain Council and of the European Federation of Neurological Associations, expressed her admiration for the IMI's approach to meeting "the grand challenge of society" that ill health represents. "This requires cooperation and partnership from a range of stakeholders," she said, and—as IMI is demonstrating—"creating high performing networks is essential." 

So far, 23 projects have been launched in 2009 and 2010. A further wave of projects, due to be launched shortly, will include autism, tuberculosis, and vaccine safety. Early in 2012, IMI will launch a new call for proposals.

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

View from Brussels

The Innovative Medicines Initative has launched several projects to improve quality of life.

An Update to Real Innovation

Contract research organizations (CROs) are working closely with pharmaceutical companies to determine where to conduct global clinical development programs. Market growth, greater regulatory requirements, increased cost pressures, and significant patient recruitment and site selection challenges have led pharmaceutical companies and CROs to make larger investments in four countries: Brazil, Russia, India, and China (BRIC).  

The BRIC countries, comprise more than 40 percent of the global population. China is now the world's third-largest pharmaceutical market, and from 2006-2009, Brazil, Russia, and India had more industry sponsored Phase II-IV trials than any other emerging country. Each of these countries represents a shift in global economic expansion away from developed countries to countries with newly advancing economies. As biopharmaceutical companies continue to expand their drug discovery, development, and commercial programs, BRIC countries will continue to be given consideration as potential areas to conduct global trials.    

One driver for growth is the large number of patients these countries offer. Large patient populations tend to be clustered in and around cities, making access to clinical trial sites easier. BRIC countries also have highly-educated, experienced investigators. In addition, BRIC governments are working to make it easier to conduct trials in country, and there is an increasing desire to commercialize compounds.  

China, for example, has more than 125 universities and colleges of medicine and pharmaceuticals with approximately seven million people enrolling in doctoral and master's study programs, giving the industry a large pool of potential investigators and researchers. However, there continues to be a shortage of experienced clinical research associates in the country. As more companies move into China, the market will continue to become more competitive.   

BRIC countries offer well-developed centralized healthcare systems; they often require fewer sites to recruit a large number of patient groups. As a result, clients are able to complete enrollment and advance development of their clinical programs more quickly.     

Clinical trials are being conducted in BRIC countries across a broad range of areas, including hematology/oncology, cardiovascular, metabolic disorders, CNS diseases, and infectious diseases. A few years ago the majority of trials were limited to infectious diseases.    

The growth of clinical research in BRIC countries has led the US Food and Drug Administration to open offices in China, India, and Latin America. While these new offices are initially focused on monitoring quality in manufacturing, inspections of research sites are being conducted and are likely to increase over time. Inspections completed in emerging markets, to date, have shown that the quality of research is in line with the developed world.  

 Executive Vice President, Global Clinical Development PPD, Inc. 

A Closing Thought

BRIC governements are working to make it easier to conduct trials in country.

BRIC Countries Contribute to Research

When my daughters were younger, we must have watched 

 together a hundred times. We never failed to be disappointed when despite all the bold words of the wizard, a look behind the curtain revealed something much less than impressive. Is the same true as we look at eClinical—bold claims, lots of talk, but little substance in reality when you drill deeper? In this article, I examine some of the success stories showing how eClinical is defining new processes and ways of working: creating a yellow brick road and not simply paving the cow path. 

As is the pharmaceutical industry, the supporting technology vendor space is undergoing huge changes. The market is consolidating with vendors extending the breadth of their offerings through acquisition or organic growth. We are observing acceleration in the pace and scale of this consolidation including the large-scale acquisition that brought RTSM (randomization and trial supply management), EDC (electronic data capture), and safety offerings to be added to one corporation's CTMS (clinical trial management system) solution. In another example, an EDC provider has been building RTSM functionality within their EDC solution, while acquiring a CTMS product to broaden their suite, essentially blending internal growth and acquisition strategies. The likely outcome is a marketplace dominated by a number of large suite providers. Each provider is working to make their collection of applications into a coherent and compelling product suite, but also ensuring their framework standards enable the inclusion of other third-party systems within their environment. 

Early trends and talk around eClinical focused around how data from disparate systems could be integrated to remove duplication of data and activities. Integration of key trial technologies is now expected and often considered a "given" by the purchasers of technology systems and services. Vendors and sponsors are responding to the need to provide and support integration at volume by developing standard infrastructure and processes to enable operation at scale. Consider global shipping of goods and cargo. Standard container and hold sizes mean that goods can easily be transferred from truck to truck and from truck to ship, seamlessly and simply. A multitude of differently shaped containers would mean time lost when transferring cargo from one vehicle or vessel to another, and suboptimal use of space as containers would be unable to squeeze into all the remaining gaps and occupy the complete hold-size available. One way in which eClinical has changed the way in which we do business is that integration of key clinical trial systems have become expected rather than exceptional. As noted above, however, to achieve this growing demand, vendors and sponsors are investing in infrastructure and standards to ensure capabilities can be scaled up and applications integrated in a rapid, efficient, and supportable manner—like the cargo industry analogy. While vendors are primarily focused on the easy integration of their own applications, most are doing so by developing integration standards that will also make interaction with third-party systems simpler. 

Although the industry to date has demanded the flexibility to select and combine applications from multiple suppliers, and hence required applications to publish open integration standards to facilitate this, there are movements in the industry where some sponsors are beginning to consider a complete technology suite as opposed to piecemeal applications. Specific applications, like EDC, are becoming more commoditized and purchase decisions are less based on feature comparison and more around other factors such as price and the associated product suite applications each can be supplied with. It is clear that compelling product suites that incorporate RTSM, EDC, CTMS, and SAE management—and provide plug-ins for key tactical solutions such as ePRO and medical imaging—are likely to see greater changes in purchasing behavior. Some providers are working beyond simple data integration to make their combinations of products more attractive than a collection of third-party applications. Areas of development include identity management—ensuring a common process and single sign on across a product suite, and product convergence—enabling functionality that resides in one application to be exposed through another to simplify user workflow. Both of these have huge advantages to sponsor and site users in the simplification of how they use multiple technology applications together in a single study or program. As vendors put in place their own identity management infrastructure, we see sponsors requesting federation with their own in-house identity management solutions so that in-house staff can access vendor systems directly without an additional logon. 

A compelling example of product convergence is the progress some vendors are making in simplifying the workflow for site users in the way they use the core trial applications of EDC and RTSM in combination. Now used in many trials this involves the access and execution of certain RTSM functionality from within the EDC application—either through web-service integration (Figure 1) or by building the functionality into EDC. Either approach involves significant product development to enable the functionality within the EDC framework, such as building RTSM events into the EDC design tools to enable events to be selected and configured and the associated EDC data required to be identified. Additional objects and forms within the EDC application enable the events to be executed in line with the user workflow in an intuitive manner. This takes the user experience beyond the benefits of data integration. 

A site user, for example, may now simply perform all patient-related tasks through a single product, their EDC application. This simplifies workflow by eliminating the need to log in and out of multiple applications to perform simple tasks, and reduces training needs as essentially all activities are completed within a single application. This popular approach may be supplemented with flexibility—enabling site users to use the telephone interface (IVR) when more convenient, as opposed to being required to use the web at all times. In this case, all data collected using IVR can be fully integrated with the EDC eCRFs. This flexibility is an advantage to certain sites that still find the phone more convenient when performing real-time activities during a patient visit. Convergence is one of the ways in which combinations of discrete applications can be made to operate in a way more valuable than the sum of their parts. 

eClinical solutions are being used more frequently in upstream site on-boarding and qualification processes, and in managing site-sponsor collaboration during a clinical trial. Portal technologies enable a simple way to deploy site-sponsor facing functionality that can greatly enhance and simplify complex processes and are a vital component of any eClinical enabling technology platform. Simple rules engines or more complex business process management solutions can guide the site user through all the steps and activities they need to complete to become ready and approved to participate in a clinical trial. These applications typically include the ability to publish and access online site feasibility and qualification questionnaires; and the exchange and sign-off of confidentiality agreements and contracts, protocols, and other essential and regulatory documents. Providing a simple interface to navigate this activity is a major benefit for site users. Rather than receiving multiple e-mails with vast numbers of attached documents for signature or retention, the site user can be simply navigated through the sequence of activities required via the inherent rules engines. In addition, having a single place to access the most recent version of each trial document eliminates the need for individuals to keep track of multiple versions. 

Some site-sponsor portals include shared collaboration spaces to enable a subset of the trial community to work together for the creation of a new document, such as a protocol amendment. Some include discussion forums, news areas, and online training capabilities. Others help to collate information to maintain and provide an electronic trial master file. Good examples presented at conferences in recent years include Novo Nordisk's investigator portal that provides an online community for investigators involved in their hemophilia trials. 

These advancements in the way technologies can be integrated and seamlessly presented together have provided the opportunity to leverage them in different and exciting ways. Pfizer announced in June 2011 that they were conducting a pilot study that would assess a completely new paradigm in the way trials are conducted—enabled because of the maturity and advancement of eClinical technologies.

  Their REMOTE (Research on Electronic Monitoring of OAB Treatment Experience) trial uses technology to allow overactive bladder patients to participate in a study of Detrol LA (tolterodine tartrate) without a requirement to visit a clinical site. This novel approach of a direct-to-patient study opens recruitment opportunities to a much wider population of patients as there is no requirement to reside geographically close to a defined study site. A patient-centred overview of this study can be viewed in a short YouTube video.

  This video explains how patients will be qualified and consented by a combination of online multimedia screening with telephone consultation by medical experts at a central study site. Participating subjects receive laboratory kits through the mail which they can take to a local clinic for tests to be undertaken. Eligible subjects receive a handheld ePRO diary by mail to record and transmit micturition data, and medication is shipped direct to their home from the single central investigational site. This approach would not be possible without the maturity of the supporting technologies and the eClinical infrastructure to integrate them seamlessly for patient, central investigator, and sponsor users. 

The final eClinical trend worthy of note is software as a service (SaaS). SaaS promises to revolutionize how software is provided within our industry as it has successfully already within other industries. SaaS enables sponsors to leverage technologies without large capital expenditure or infrastructure investment. Hosted by a third-party, SaaS solutions often leverage multi-tenancy properties of the software applications to enable infrastructure costs to be shared effectively across customers and hence reduce the cost of hosting by sharing the expense across multiple clients. Pricing models often follow a per-usage approach, which eliminates the large capital expenditures that are commonplace when purchasing software solutions for on-premise installation. 

These approaches are attractive to smaller and mid-sized pharmaceutical companies who seek to leverage technologies without the need for infrastructure and software investment, but are also showing appeal for the larger pharmaceutical companies who are looking to the cloud to reduce internal costs. Many technology vendors are seeing SaaS as a vital industry trend and we expect to see the development of increasingly greater SaaS capabilities serving our market over the coming short-term horizon. 

eClinical-enabled clinical trial processes truly are becoming a way in which our industry is now doing business to leverage the true values of technologies and achieve greater productivity and efficiency gains in development. There is genuine excitement about what new developments we will see in the coming months and years that will continue to push the boundaries, create compelling product suites, make sustainable and scalable integrations, further simplify workflow through product convergence and new applications, and make technology more accessible through SaaS programs. As the Wizard of Oz himself said, "[we] should consider ourselves lucky [to be granted] an audience tomorrow instead of 20 years from now." In fact, as this article has demonstrated, we can see the impact of eClinical today—on our processes, how we use technology, and what we expect from it. 

is Senior Director of Product Strategy, Perceptive Informatics, Lady Bay House, Meadow Grove, Nottingham UK, e-mail: 

1. Jennifer Corbett Dooren, "A Clinical Drug Trial Via Phone, Computer," 

http://online.wsj.com/article/SB10001424052702304432304576369840721708396.html

, "Mytrus 16-wk Paid Overactive Bladder Clinical Trial for Women," 

http://www.youtube.com/watch?gl=GB&v=0fEx5V45zp4

Feature Article

Examination of eClinical shows that it is more than just bold claims, there is substance.

eClinical: A Yellow Brick Road?

Site per visit increases have been smaller in recent years. To a large extent this may be a function of the number of sites that are being opened in non-traditional, less expensive geographies. According to GrantPlan®  and 

, a growing number of clinical studies are using sites in areas such as Latin America, Asia, and Eastern Europe. In addition, the total number of new sites opened in the last 12 months around the world has been fairly constant. The recent relatively flat overall increased demand for sites, coupled with the continued shift of clinical trial work to less expensive geographies have combined to reduce the demand for clinical investigators. Consequently, sites around the world have less ability to command higher prices. 

 Mean cost per visit in Phase II-III clinical trials. 

GrantPlan subscribers conduct nearly 80% of all commercial clinical trials around the world, with each company contributing the active grant agreements to the database. On a cost per visit basis, site costs have risen or stayed relatively flat in the various major geographies for conducting clinical trials. The United States continues to be the most expensive country in which to conduct clinical trials, followed by the United Kingdom and Western Europe. Just as importantly, the difference in per visit costs between the traditional and newer geographies continues to exist. Latin America, Asia, and Eastern Europe continue be lower priced areas for clinical grants. 

Site per visit increases have been smaller in recent years.

Clinical Grant Expenditures are Stabilizing

Drug shortages have been front-page news in recent months as physicians, pharmacists, and patients voice outrage over disruptions in the supply of medicines to treat cancer, pain, and other serious conditions. Oncologists can't obtain widely-used generic injectables to treat critical patients. Surgeons are postponing operations because they lack key anesthetics and pain medications. Doctors are struggling to obtain vital parenterals for premature babies and for patients requiring infusion. 

The Food and Drug Administration (FDA) is responding by exercising flexibility in enforcing manufacturing standards and speeding the approval of alternative products and production lines. Such efforts can help sponsors of cancer and AIDS trials avoid shutdowns due to short supplies of key products used as comparators or in treatment cocktails.  

Similarly, FDA officials emphasize flexible approaches for developing and approving innovative therapies to treat rare disorders. Agency critics often cite excessive FDA regulation for driving up the cost of drug development, but FDA officials maintain that they frequently bend the rules to speed new products to market, both to facilitate access to short-supply medicines or to spur research and development of orphan drugs. 

FDA recorded 178 drug shortages in the United States in 2010, up from 157 in 2009—and much more than the 50 to 60 range of previous years, reported Edward Cox, coordinator of the drug shortage program in the Center for Drug Evaluation and Research (CDER). The main culprit appears to be drug manufacturing and supply chain issues, particularly related to production of generic sterile injectables, Cox explained at an FDA public workshop held in September for health professionals, patient advocates, biomedical researchers, and manufacturers to air concerns and propose remedies for the supply crisis. Industry consolidation, lack of raw materials, changes in distribution practices, and business decisions to discontinue certain products all contribute to the current drug supply crisis. Some observers also blame FDA for being overly strict in enforcing manufacturing standards and for ignoring the potential harm of shortages in calculating risks and benefits of regulatory actions.  

One less-noticed aspect of the drug shortage crisis is its impact on clinical trials. Shortages in generic cancer therapies are shutting down oncology studies because investigators cannot obtain adequate supplies of drugs used as controls or in combination for treatment arms. More than 150 trials sponsored by the National Cancer Institute (NCI) are plagued by shortages. Many sponsors have halted patient accrual for fear they might have to switch to a new comparator or treatment components, which could compromise data later on.  

Many of the cancer drugs in short supply—including doxorubicin, daunorubicin, 5-FU, paclitaxel, bleomycin, and cytarabine—are essential to treatment and research, explained Howard Koh, Assistant Secretary for Health in the Department of Health and Human Services, at a hearing in September before the House Energy and Commerce Health subcommittee. NCI currently is sponsoring 96 clinical trials that include combination or control arm drug regimens that require a supply of doxorubicin, and even more involve the use of paclitaxel. A shortage of only a few weeks can have "a ripple effect on the availability of new drugs and treatment combinations tomorrow," warned Robert DiPaola, Director of The Cancer Institute of New Jersey.  

Shortages also are a major issue for AIDS clinical trials supported by the National Institute of Allergy and Infectious Disease, Koh pointed out. Supply problems involving liposomal doxorubicin (Doxil) made by the Janssen unit of Johnson & Johnson, as well as short supplies of first-line antibiotics to treat life-threatening infections associated with AIDS, are blocking studies that seek to compare different AIDS regimens.  

Policy makers are reviewing the full range of relevant factors, including whether too-low reimbursement for old-line generics discourages industry investment in this market. Congress also is looking to enact legislation that will prevent shortages by requiring manufacturers to notify FDA six months in advance of anticipated changes in prescription drug production.  

Additional remedies may arise from analyses of the shortage crisis from both FDA and the Government Accountability Office.  

In some shortage situations, clinical trial sponsors can utilize alternative regimens, even if these are not part of the original protocol. However, such changes often expose patients to more toxic or less effective treatments. New consent forms may be required, and sudden changes in site and therapy discourage patients from participating in research.  

The broader solution lies in efforts by manufacturers and FDA to prevent drug shortages through compliance and regulatory actions. Agency officials maintain that they don't halt production for minor violations, but for significant problems with drug sterility and contamination, such as metal particles in vials and new impurities and degradants. In addition, the agency says it can bend the rules to permit continued marketing of a violative product.  

By exercising regulatory flexibility, FDA has been able to expedite the review and approval of supplements authorizing new suppliers and manufacturing changes. Advance warning of likely supply interruptions helped FDA head off 38 potential shortages in 2010, and 99 so far this year. And the agency has had success in encouraging other firms to ramp up production or to enter a market.  

Regulatory flexibility also is key to FDA approval of new treatments for rare diseases, according to research sponsored by the National Organization for Rare Disorders (NORD). FDA legally requires "substantial evidence" of effectiveness to approve a new drug for market, which traditionally has meant two or more well-controlled clinical trials. But the agency frequently modifies the scope of study data needed to develop an innovative therapy for a serious condition. Many treatments for rare disorders have been approved based on relatively few patients in only one clinical study.  

An analysis of 135 non-cancer orphan drugs approved by FDA from 1983 to mid-2010 by Frank Sasinowski, attorney with Hyman, Phelps, & McNamara and NORD Chairman, shows that 90 therapies benefited from more flexible regulatory approaches. At last month's conference on orphan drugs sponsored by NORD and the Drug Information Association, Sasinowski presented his report as evidence that FDA has not become more conservative, but has a strong history of using a variety of strategies to facilitate the approval of critical new drugs. 

FDA applauded the analysis, hoping it will help fend off criticism from industry and the investment community that agency regulatory policies are dampening investment in new drug development. CDER Director Janet Woodcock acknowledged that orphan drug development requires flexible regulatory standards, citing previous agency adoption of more moderate rules for producing clinical supplies in small quantities and for reduced toxicity testing for very small early clinical studies. Woodcock noted that FDA has approved many orphans with only one clinical trial and that it plans to update its 1998 guidance on substantial evidence to further clarify this approach. The NORD analysis of the agency's history in dealing with orphan drugs over nearly 30 years, she added, will be "extremely helpful."  

Alternative approaches aim to tackle drug shortages, spur orphan drug development.

Applied Clinical Trials-11-01-2011