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Applied Clinical Trials Digital Edition - July 2010, Supplement

SITES : Incorporating Standard of Care in Study Budgets  Benefits of CTMS at the Investigative Site  Also in this issue : FDA Transparency Efforts to Impact Research, Survey Assesses Europe?s Clinical Trials Directive, Tapping into the Potential of Pharmacists, Biosimilars Make Headway in the U.S.

Applied Clinical Trials Digital Edition - July 2010

Fifteen years. That is the time it took from when Amgen accidentally discovered via big mice an "essential pathway that regulates bone metabolism" to the FDA's approval last month of Prolia for the treatment of osteoporosis in postmenopausal women at high risk for fracture. Amgen is currently recruiting in Phase III trials for the same treatment and indication in men. NCT00980174 is the 

Prolia, or denosumab, is unique in that it is the first and only RANK Ligand inhibitor approved for this indication. In addition, denosumab is the first biotechnology product to be approved for osteoporosis. As an anabolic, it builds up organs and tissues using naturally occurring metabolic pathways, or in this case, the RANK ligand inhibitor blocks the bone loss imbalance caused by the RANK ligand and allows denosumab to mimic bone-protecting effects of a specific protein. 

Colin G. Miller, PhD, Senior Vice President of Medical Affairs at BioClinica (Newtown, PA), spoke to 

 about Prolia and osteoporosis clinical trials in general. "Anabolic compounds actually change the bone metabolism rather than bisphosphonates, which stick in the bone to prevent or reduce osteoclastic resporption," explained Miller. Because of this mechanism of action, Prolia is considered superior to the bisphosophonates. 

The most popularly known bisphosphonate is Fosamax (Merck), which fell off the patent cliff February 2008, is generic, and grouped with Boniva (Roche and GlaxoSmithKline) and Actonel (Warner-Chilcott and Sanofi-Aventis). These are the oral formulations and are associated mostly with gastrointestinal (GI) side effects. These tablets can be taken once a day, once a week or once a month. Considering that the patient is recommended to stand for at least 30 minutes after dosing, the once a month option is probably better for lifestyle issues. Novartis' bisphosphonate Reclast is a once-a-year injection, so it bypasses the GI issue. 

However, Prolia is a twice-yearly injection, which as far as formulation and lifestyles go, is a good thing toward compliance. Here's a negative for compliance: the ability to pay. Prolia will cost approximately $850 per injection. 

While shares of Amgen rose on the news of its back-to-back U.S. and European approvals, and positive feelings based on the first biotech approval in this area with success after a long clinical trial process, the current payment atmosphere is not so glowing. 

Here are some basic facts on osteoporosis, according to the International Osteoporosis Foundation: 

One in three women over 50 will experience osteoporotic fractures, as will one in five men. 

Osteoporosis affects an estimated 75 million people in Europe, the United States, and Japan. 

By 2050, the worldwide incidence of hip fracture in men is projected to increase by 310% and 240% in women. 

Nearly 75% of hip, spine, and distal forearm fractures occur among patients 65 years old or over. 

The peak number of hip fractures occur at 75 to 79 years of age for both sexes. 

All these statistics sound like a positive for the pharmaceutical industry as far as potential sales go. In fact, the global osteoporosis market has been forecast by Research and Markets to be worth between $8 billion to $10 billion this year and nearly $14 billion by 2014. 

According to Miller, the picture becomes a bit cloudy on the post-fracture outlook. After a hip fracture, the typical prognosis for the 75+ is approximately 20% will go on to fracture the second hip, about 20% are likely to have increased morbidity, and 20% will die. Therein lies the problem for prescribing medication after the diagnosis. The disease has already progressed too far and now spills into the cost benefit and quality-of-life issue spectrum. 

Most 75 to 80-year-olds in the United States have their drugs paid by Medicare. With the likelihood that Medicare would prefer to pay the generic prices of a bisphosphonate vs. the injection of a superior anabolic at a higher price point, Amgen may be facing longer-term struggles toward the success of Prolia, which has projected sales of $1 billion a year by 2012. In fact, Amgen is evaluating Prolia in metastatic bone disease in the United States so that it will be able to take advantage of the bone loss issue caused by over-expression of Rank Ligand in some cancers, where analysts predict it may actually make more money. The European Commission approved Prolia—in addition to the osteoporosis in postmenopausal women indication—for bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. GSK will co-market the drug in Europe and the rest of the world. 

Oncology indication aside, in order to find the people who would most benefit from a preventive drug before the disease progresses, a strong biomarker would be needed. 

"Four years ago, we were approached by Novartis to help find a better biomarker to predict spine fracture, and help enrich the population used in trials," Miller said. In fact, at press time, BioClinica and collaborators, Novartis and Optasia Medical (Manchester, UK) were finalizing their joint press release on their results, which have appeared in the medical journal 

Those results are now being used in a five-year epidemiological study to see if the process can accurately predict spine fracture as the potential process has shown. This process is using modeling or simulation software that can read x-rays to identify vertebral deformities or abnormalities that it models based on an initial development and placement of 88,000 discrete points taken on lateral spine X-ray films from 150 subjects. 

Miller said there were other biomarkers in development, which could help spur the current stasis of the osteoporosis clinical trials market, including fractal analysis and finite element analysis. While not the most robust of therapeutic areas, there are osteoporosis drugs in development on hold out there in Phase II and Phase III. And these are more likely to be smaller companies that are waiting on funding. This would include Radius Health's PTH BA058 (parathyroid hormone), which also builds bone and concluded Phase II trials successfully in August 2009. It has a 

And funding is not easy to come by for biotechs these days, or osteoporosis trials for that matter. Miller says osteoporosis is one of the most expensive therapeutic areas in which to conduct a Phase III trial. Miller listed the factors, including: a high number of patients to power the trial, between 3000 and 4000, who then need a DEXA test, spine films, and blood draws that are all centrally read, as well as visits every three months. The trials run for a minimum of 18 months and go to at least three years. 

Factor in that the average price for the cost per patient for Phase III trial, without the multiple criteria stated above is $26,000. Factor in that for every patient enrolled, five are screened. The Prolia Phase III trial, NCT00089791, consisted of 7808 subjects. "A pharmaceutical company could develop two analgesics for one osteoporosis drug," said Miller, by way of comparison.  

But for those companies willing to continue to tackle the hurdles of osteoporosis drug development, the way may be paved with biomarker development. Drugs in development include different drug deliveries or formulations (i.e., a nasal spray). Some are reformulations of calcitonin, which has been available for quite some time and is a hormone that affects blood concentrations and calcium. Another compound based on PTH is in development by Novartis, following on Forteo from Lilly, which was the first approved PTH and is delivered daily via pen injection. 

FRAX, or the fracture risk assessment tool, is a free online fracture-risk calculator that was developed by the World Health Organization Collaborating Center for Metabolic Bone Diseases at the University of Sheffield, UK. The online tool itself can be accessed at 

. However, the future is calling and the FRAX developers have made the tool available for the Apple iPhone. 

The FRAX algorithms give a 10-year probability of fracture. The model was developed from information on fracture risk factors from 12 prospectively studied population-based groups in diverse geographic regions, including North America, Europe, Asia, and Australia. As mentioned, the tool is available online as well as for the iPhone (but not for iPhone 4.0 yet), and as a downloadable one-page, two-sided questionnaire in PDF format. 

The iPhone application was launched this past May in Florence, Italy, during the World Congress on Osteoporosis 2010. It is anticipated that the FRAX iPhone app, selling for $5.99, will "vastly increase the accessibility of the FRAX tool to thousands more physicians and health care practitioners worldwide." 

According to Colin G. Miller, PhD, Senior Vice President of Medical Affairs at BioClinica (Newtown, PA), the FRAX tool builds in multifaceted information to make for more robust and accurate identification of fracture risk. Miller said that more European agencies are adopting the FRAX criteria for fracture risk as an end-point in clinical trials, and believes that ultimately it will be adopted more widely in the United States. 

Phase News

Updates on Osteoporosis including Amgen and Prolia trials.

Osteoporosis Clinical Trials, Not for the Faint-Hearted

Personalized medicine has become one of the buzz phrases in global health care over the past couple of years, and it is being used increasingly in the drug development field. But what exactly does it mean? And does the term have any great relevance for clinical trial organizers? 

Conference organizers are now attempting to provide some answers to these and other controversial questions. They are honing in on the potentially lucrative area of personalized medicine, and October promises to be a bumper month for meetings. In the United States, the Third Annual Personalized Health Care National Conference will take place in Columbus, Ohio, October 14-15. During the same week, the United Kingdom will host "Personalized Medicine: The Collective Approach to Individualized Healthcare," which will be held October 11-12 at London's Crowne Plaza City Hotel. 

In addition to the latest science and R&D trends, the program for the London event will look at business strategies and legal issues for developing personalized therapeutics and introducing them to the marketplace. Speakers will discuss how to identify and develop validation biomarkers as tools for personalized medicine, and how to use stem-cell technology to implement a more personalized therapeutic regime. They will also focus on successful partnerships, regulatory challenges, deep resequencing as a tool for drug repositioning, and integrating biomarker discovery and execution. 

Initially, experts thought personalized medicine referred merely to targeted therapy, but many people now view this definition as too narrow. For instance, on the Lab Soft News Web site in February 2010, Brian R. Jackson, MD, Medical Director of Informatics at ARUP Laboratories, noted that personalized medicine should be thought of in terms of the information integration necessary for patient care. 

"The two ends of the spectrum in my mind are population medicine and personalized medicine. Population medicine is essentially evidence-based medicine. It gets criticized for being cookbook, but the fact is that there is important information value in studying large groups of patients at a time—think where we'd be if randomized clinical trials didn't exist," he wrote. 

At the other end of the spectrum is personalized medicine (i.e., acquiring and integrating more and more patient-specific information). Jackson believes real progress will be made when we figure out how to properly balance and take advantage of both population-based information and personalized information and apply that to individual patients. 

For those keen to learn more, there are numerous Web sites devoted to the subject, including the well-resourced Personalized Medicine Coalition (PMC). This coalition aims to educate federal and state policymakers and private sector health care leaders, helping them understand the science, the issues, and what is needed for the evolution of personalized medicine. 

According to its mission statement, the PMC collaborates with member organizations and outside experts to identify, analyze, and address the ethical, legal, and social implications of personalized medicine. It provides a forum for debating and reaching consensus on public policy issues, and educates policymakers and health care leaders about the importance of personalized medicine and its evolution.  

Additionally, it serves as an umbrella organization for stakeholders who are conducting personalized medicine education in both the public and private sector, and provides networking opportunities for the many and varied stakeholders. 

				Once the conferences have taken place this October, the future outlook and prospects should become much more clear.—

Global News

Global Trials Get Personal

Act cover

CROs conduct a substantial, and growing, percentage of clinical trials for sponsor companies. Drug development professionals in sponsor companies have sometimes voiced concerns about how clinical sites view working with CROs, particularly as it relates to the consequences of CRA turnover and a possible lower level of in-depth study compound knowledge.

 CRO or Sponsor: Site Preferences for Trial Management			

An in-person, mail, and Web-based global study of over 4000 sites demonstrates that investigators have largely come to accept CRO study management as an integral part of today's clinical research. More investigators prefer CRO management (29%) to sponsor company direction (23%). The largest number of investigators though (48%) do not care whether a CRO or sponsor company runs a study in which the investigators are participating.   

The general pattern does not vary appreciably by type of site. For instance, sites such as academic medical centers and teaching hospitals, that many might expect to prefer sponsor company project management, do not. Only 18% of these investigators prefer sponsor companies over CROs. Most (54%) are indifferent between sponsor companies and CROs. The desire to work directly with sponsor companies is highest in North America (31%). Yet, investigators of all types who do prefer to work with a sponsor company are not willing to accept even a slightly lower cost per patient grant to work with these companies rather than CROs. For many investigators CRO study management is an accepted fact of their clinical research activities.

Do Sites Prefer a Sponsor Company or CRO to Run Their Clinical Trial?

  One of today's most important emerging regions for clinical trials is Latin America, which is being increasingly considered for trials because it offers significant potential.

Regulatory enforcement bodies, quality investigators, ethics committees ensuring patient safety, proactive Good Clinical Practice (GCP) policy development, and huge research naïve populations have been cited as contributing to Latin America's explosive growth.

  Yet, as in many regions, important challenges remain, including language and cultural barriers.

Regardless in what country or region a clinical trial is conducted, successful trials can be determined by a number of factors, including:   

Experienced and efficient investigational teams

The presence of a target patient population willing to participate in trials

Epidemiologic considerations around disease and prior treatments

Updated regulations in conjunction with adequate approval timelines (see sidebar)

The health system and overall standard of care

Ethical committees, which work for the safety and respect of participant patients

So why has Latin America become such a hotbed of clinical trial activity? Many Latin American countries possess each of these success factors, which we'll discuss. 

One of the most important factors in conducting a successful trial is the quality and enthusiasm of the investigators. Because clinical trials are relatively new in Latin America—within the past 20 to 30 years—investigators tend to treat participation as more novel and interesting than their counterparts in other countries where trials have been occurring for a longer period of time. Many of these investigators place a high value on the scientific and academic aspects of the trial, and are pleased when they are invited to participate. 

However, don't mistake enthusiasm or novelty for inexperience. As Latin America became recognized for its enrollment potential and the high quality of the data obtained, the number of clinical trials started in the three largest countries in the region increased significantly over the past five years. For example, the number of clinical trials started in Brazil has increased 58% (from 153 in 2005 to 241 by 2009). In Argentina, the growth in new trial starts is more modest at 16% (from 97 to 112 over the same period), while Mexico has achieved a 49% increase in new trial starts (from 106 to 158 over the same period).

This growth, combined with other factors, has led to the proliferation of educational forums where investigators are schooled in all aspects of clinical research. For example, in Argentina courses are offered at the Instituto de Biología y Medicina Experimental, Universidad Austral, and Fundación de Estudios Farmacológicos y de Medicamentos.

  In Brazil, courses are frequently offered by the Brazilian Society of Pharmaceutical Medicine and the Brazilian Society of Clinical Trials. Many Latin American countries require that investigators, study coordinators, and nurses take certain courses. Certification is planned to be requested by some regulatory authorities, such as the Argentina Ministry of Health, for physicians proposed as principal investigators.

An advantage of Latin America is that it has densely populated areas, with an increased likelihood that subjects will meet the prerequisites for the trial. For example, the greater metropolitan areas of cities like São Paulo (11 million), Rio de Janeiro (5 million), Buenos Aires (13.4 million), and Mexico City (21 million) provide access to a broad range of potential study participants. Latin American countries also offer a wide ethnic diversity, due to significant immigration from Europe, Asia, and Africa.

The doctor/patient relationship among Latin Americans is very strong, leading to a high level of willingness to participate, compliance, and retention throughout the course of a trial. As people learn more about the benefits of clinical trials, such as gaining access to new therapies and receiving better medical care, they are also more eager to participate. Finally, in the authors' experience, many Latin Americans are motivated by the altruistic aspect of contributing to the body of knowledge around the drug or treatment. 

As with any clinical trial, it is important to understand the epidemiologic features of a region before locating a study there. For example, both Chile and Peru have a high incidence of gastric carcinoma.

  Gallbladder cancer is also frequently seen in Peru.

  The incidence of cervical cancer and other HPV-related tumors is high across Latin America. Other types of tumors, such as breast, lung, and colorectal have incidences similar to the United States and Europe.

Infectious diseases like tuberculosis and HIV are still a challenge even though there are concerted efforts to reduce transmission.

  Finally, seasonal diseases like pneumonia and flu occur at different times of year in the southern hemisphere relative to the northern hemisphere, making Latin America a well-suited region to conduct infectious disease studies, with a seasonal component so that sponsors don't have to wait to conduct their trials. 

Health systems vary from country to country, but most have a distinction between public and private institutions. Either type can conduct clinical trials, although there are going to be epidemiological, social, and cultural differences in the type of population being assisted. These factors will be relevant when performing site selection in connection with a specific clinical trial. 

The standard of care for different pathologies and procedures is about the same as that found in the United States or Europe; new drugs are commercially available in most Latin American countries, although they may not be affordable for all segments of the population. This makes it possible both to find patients who have been on a previous treatment and to find those that are treatment naïve. 

No examination of global clinical trials would be complete without a close look at the ethical considerations involved. One area of significant concern is the fact that some Latin American populations are poor, illiterate, and without access to regular health care. This type of participant is especially vulnerable, highlighting the complications around enrollment, even with careful attention to informed consent. That's why the role of the ethical committees in reviewing and approving the proposed trials is so critical and relevant.   

Ethics involving the conduct of the trial and the safety and welfare of the patients are paramount. They emphasize that sponsors and CROs must carefully select investigators and staff who are committed to protecting the patient. Investigators and staff must be able to inform patients while not coercing them. Ethical committees must audit participant sites to ensure that study subjects are adequately protected. 

Sponsors and CROs, in partnership with the ethical committees and regulatory authorities, are obliged to review every study protocol from an ethical perspective particularly around the informed consent form. Informed consent is the best tool available to balance the patients' trust in their physicians with the ethical considerations of their participation in the study. Extra care is needed when patients may be poorly educated or may have no other options for treatment. All parties involved in the study have the obligation to ensure that the consent form is written and presented in a way that is understandable to the patient. 

Despite the clear benefits of running trials in Latin America, there are also some significant challenges to consider before starting. One of the most difficult, given that most studies originate in countries outside of Latin America, is language. Not only is careful translation critical to the logistics and procedures involved, it is even more crucial to ensuring the safety and ethical treatment of study participants—particularly in the area of informed consent. 

Although most of Latin America speaks Spanish (with the exception of Brazilian Portuguese), there is a tremendous amount of local variation in the meaning of some words, which makes them quite different from standard Castilian Spanish. This requires a deep review by local people in order to guarantee that both site staff and patients understand everything required during the trial. 

In addition to language differences, there are regional and cultural differences that come into play. Latin Americans' relationship with their physicians tends to make them more trusting and unquestioning; they'll listen to their doctors without some of the pushback seen in other Western nations. Patients may participate more willingly in trials because of their doctor's recommendation, but there needs to be a careful balance between the actual benefit to the patient and their desire to please their doctors. 

 Don't underestimate the time it will take to go through the regulatory and import process. Particularly in Brazil, it takes longer to start than in other countries. However, changes put in place in December 2009 have reduced the review timeline process by about six to eight weeks.

 Due to the nature of the regulatory process in Latin American countries and the cycle time to trial approval it is vital to submit documentation correctly the first time. Take the time to thoroughly review all documents two or three times to avoid mistakes. It may also help to have a checklist for sponsors so they understand the detailed documents that must be provided for the local and national regulatory packages. Documentation checklists are highly variable dependent on the country in which the trial is being conducted, the type of trial, and many other factors. 

 Take time to understand how all parties like to work and what they prefer as a communication channel. The use of email should be carefully considered with respect to language and culture differences. Email is a powerful tool, but can also lead to misunderstandings, so it is important to pick up the phone often to ensure clarity on important issues. Invite sponsors to visit potential sites, since it may be difficult for someone who hasn't been in the region to understand the capabilities of the area. Seeing the facility and talking to the investigators and staff are great ways to learn more about how things are conducted. 

 It is particularly important to have someone local involved with the trial who understands and can address regional issues and how cultural differences could affect participation. For example, patients must clearly understand that they may not receive a direct benefit by participating in the study. Patients' willingness to participate is connected to their understanding of the process, education, and values, which might vary regionally. 

 To be successful in Latin America one must have an authentic respect for culture, custom, and language when conducting global trials. Local resources will likely have a greater understanding of this than study sponsors. For example, the local managers understand specifically what the ethical boards are looking for in the informed consent and have developed templates. Sponsors that have insisted their own wording be included in the informed consent form have often had those forms rejected. 

Global clinical trials are best served by recognizing, valuing, and respecting the diversity of every region involved. It pays to learn more about what Latin American countries have to offer, and which of them best fits the needs of a specific study. There are many experienced clinical research professionals in Latin America who can guide study sponsors in areas such as population demographics, regulatory timelines, and regional capabilities. It pays to listen to these regional experts for the best possible outcome of a Latin American clinical trial. 

,* MD, is the Managing Director, Latin America, email: 

, RPh, MBA, is the Managing Director, Brazil, at Clinipace Worldwide.

*To whom all correspondence should be addressed.

1. R. Chin and L. Safar, "Clinical Trials Go Global: Next Stop, Latin America," 

http://www.msal.gov.ar/htm/site/default.asp

Feature Article

An overview of the clinical research landscape in this emerging region that also looks at its challenges.

Trials in Latin America

 MD, as senior medical director in its oncology practice.  

(Princeton, NJ) as Scientific Director Bioanalytical Services.  

(Baltimore, MD) Senior Director of Biometrics Consulting, 

, PhD, will lead its consulting team as it works with pharmaceutical and biotechnology companies to address biometric issues associated with clinical trial submissions.  

(King of Prussia, PA) Project Management Team, will guide client clinical teams in assessing the impact of study design on patient recruitment.  

(Princeton, NJ) has expanded its Phase IV development team with the additions of 

as Executive Director of Observational Research, 

 as Executive Director of Health Economics and Outcomes Research, and 

as Executive Director of European Operations.  

will use his 34 years of experience in management positions in his new role as Chief Executive Officer at 

Governing Board of the Innovative Medicines Initiative 

(Brussels, Belgium), a public-private partnership between the EFPIA and the European Union. 

, PhD, as Senior Vice President and General Manager of its Concord, Ohio, facility. 

 PhD, has a new position as Non-Executive Chairman of 

 (Nottingham, UK), a Biomarker detection company. 

 (Dallas, TX) Vice President of Business Development. 

(Cambridge, MA) has hired several new members to join its team, including

 as Executive Vice President and Chief Financial Officer, 

 as General Manager for Philippines Operations, 

 as Director of Product Implementation, and 

 as Director, Product Management, SCM Solutions. 

With more than 12 years of experience in the pharmaceutical industry in both the United States and Singapore, 

has been appointed the Director of Business Development for 

Kaiser Permanente's Southern California Permanente Medical Group

 (Pasadena, CA) have formed an alliance to help accelerate the development of new and more effective medicines.

In order to accelerate time to market for new medicines and treatments, 

(Tokyo, Japan) have formed a strategic alliance.

(Boston, MA) has selected the OnCore system by 

 (Madison, WI) for its integrated clinical research management system.

 (Lansdale, PA) won the Greenest Exhibitor Award for the second year in a row at the DIA's EuroMeeting in Monaco. 

Accelovance accepts the "Best Contract Research Organization" award for the second year in a row at the 2010 World Vaccine Congress, held in Chantilly, VA.  

For exceptional growth in overseas markets, 

(Cheshire, UK), an independent provider of medical communications and drug development consultancy services, has been awarded a Queen's Award for Enterprise 2010 in the International Trade category.

(Craigavon, Northern Ireland) has won two distinctions from the 10th Annual Belfast Telegraph/BMI Northern Ireland Business Awards: the 2010 business award for innovation and a commendation in the exploring achievement category.

(Plymouth and Kalamazoo, MI) has been recognized as one of the 2010 "Michigan 50 Companies to Watch," an awards program sponsored by the Edward Lowe Foundation, as well as a "Catalyst Award" from Southwest Michigan First for creating jobs and economic success in the Kalamazoo Region in 2009.

The Association of Clinical Research Professionals awarded the 2010 Innovation in Clinical Research Award to 

(Philadelphia, PA) with the Outstanding Chapter Award at the 2010 Global Conference and Exhibition in Tampa.

(Princeton, NJ), a provider of compliance and knowledge management solutions to several pharmaceutical, medical device, and biologics companies, has won the Brandon Hall Gold Award for technology excellence in the Compliance Training category.

Receiving the "Best Contract Research Organization" award for the second consecutive year, 

(Rockville, MD) was awarded the distinction at the 2010 World Vaccine Congress held in Chantilly, VA.

(Glasgow, UK) has been awarded Women Business Enterprise certified status by WEConnect Europe.

Statprobe business unit has received the 2010 Lilly Global Supplier Award in the Supplier Award for Excellence category; i3 Spain was named one of the top 10 places to work in Spain among companies of 100 to 250 employees by the Great Place to Work Institute Spain; and i3 France was ranked number 11 in the 2010 Best Workplaces France list, also compiled by the Great Place to Work Institute.

(Craigavon, Northern Ireland) has been honored with a 2010 Great Place to Work Institute UK award.

President and Chief Executive Officer of 

, PhD, is a finalist for the Ernst & Young Entrepreneur of the Year 2010 Award in San Diego for the second year in a row.

The Observational Medical Outcomes Partnership announced the winners of the OMOP Cup methods competition, awarding 

(Orlando, FL) the $10,000 prize for Challenge 1 and also honored a 

 (Iowa City, IA) health informatics team comprised of 

 (Tampa, FL), has been awarded first place as U.S. Clinical Researcher of the Year in the CRA/site manager (less than four years) category, winning a $1000 prize from 

 (Wilmington, NC) contract research facility in Athlone, Ireland, manufacturer licenses that support investigational medicinal products and marketed products and provide laboratory certifications for quality control of medicinal products.

The Patient Recruitment Organization Steering Committee

, as a place for industry professionals, businesses, and other stakeholders to build alliances and share information.

(Morrisville, NC) has been awarded four new client projects across multiple therapeutic areas, including oncology, immunology, and gastroenterology.

 (San Diego, CA) celebrates its 15th anniversary this year.

(Cary, NC) has released an accelerated POC study design that combines single ascending dose, multiple ascending dose, preliminary food effect, and proof-of-concept studies.

(Buena Park, CA) received full accreditation status from the Association for the Accreditation of Human Research Protection Programs.

 (Tustin, CA) has expanded into the dermatology therapeutic area with 

, PhD, leading the new Dermatology Clinical Research Group.

(Lincoln, NE) has launched a new Hybrid Phase I/ECG Core Lab to provide ECG analysis for Celerion's global Phase I clinical network.

(Shanghai, China) in order to offer clients more comprehensive services in the Asia Pacific region.

Business News

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

Business and News Update July 2010

Unbelievably, the jury is still out. Has the 2001 European Clinical Trials Directive failed to make Europe more attractive for clinical research? Worse, is it hindering important clinical trials because it has increased the regulatory complexity, administrative burden, and related costs without improving safety of trial participants? After a decade, it is indeed remarkable that these questions should still be under intense assessment in Europe. Yet they are. Intensely and intensively.  

That indefatigable champion of good sense in good clinical practice, the European Forum for Good Clinical Practice (EFGCP), has assiduously surveyed the beneficiaries (or victims) of the EU legislation, and has compiled a series of answers, which it has discussed at length with stakeholders and is now passing on to the European Union authorities. The key difficulties were found in clinical trial authorization procedures, ethical review, sponsorship, ensuring risk-based decision-making, and safety reporting. 

After an extensive series of workshops to explore the difficulties and possible solutions, it has now passed on its recommendations to EU officials. They, in turn, are in the very early stages of what is likely to be a long revision process of the legislation. 

This column will examine the EFGCP findings in detail in a subsequent issue. But it is instructive to give an indication of the sort of issues that still remain unresolved about the merits and demerits of the legislation in the nine years since it was adopted—as revealed by the areas that EFGCP saw fit to explore in its survey. 

The questions still open include whether the current system of parallel reviews and approvals by all national competent authorities involved should remain for multinational clinical trials, or should be replaced by a single clinical trial authorization. And if a single authorization is to emerge, should this be obtained through a central application and central review (for instance at the EMA) or through a central application and a decentralized review—either requesting review from all authorities involved by the trial or by one authority chosen by the agency for its relevant expertise? 

Should sponsors be allowed to apply to any national authority, which would act as rapporteur for a mutual recognition procedure? And should current and new procedures for authorizing multinational trials run in parallel, leaving the sponsor free to choose their favorite option? 

Should a single application dossier, submitted centrally, be considered complete, with no possibility of additional national requests for documents? And—as ever in the linguistic patchwork quilt of Europe—what languages should a single dossier be submitted in? English? Or national languages? 

The ranking of which areas need clearer definitions varies from stakeholder to stakeholder—so EFGCP has tried to establish the good, the bad, and the ugly among the current definitions for sponsor, investigational medicinal product, substantial amendment, and noninterventional study. 

It also assessed views on whether the current definition of a single sponsor for a trial should remain, or whether there should also be options for cosponsorship, with the coordinating sponsor retaining legal and penal responsibility, or for joint sponsorship, sharing legal and penal responsibility but with a single protocol, single trial identification number, and single database. 

The survey sought views on whether there should be the same liability insurance conditions for trial participants in all EU countries, and whether it should be covered by the national health care system or a common fund (such as industry-run) rather than by an insurance company. 

Opinions were canvassed on whether multinational trials should be supported by funding mechanisms at a European level (such as through a European version of the U.S. National Institutes of Health), and whether public–private collaboration should be promoted by clearly defining rights, obligations, and responsibilities of the co-sponsorship partners at a European level. 

Areas of enquiry also extended to the desirability (or otherwise) of a more harmonized ethical review process in the EU, of raising the quality of ethical review, and of harmonizing it through accreditation and training of ethics committees. Views were gathered on whether a single ethics review opinion should remain for each EU member state, or whether this should apply only to single-center and national multicenter trials, with a single Europe-wide opinion for multi-national trials. The questionnaire also probed responders on where greater clarity was needed in what should be dealt with by ethics committees and which by national competent authorities. 

Should there be only one single expedited entry of suspected unexpected serious adverse reaction reports into the EU's central EudraVigilance database, or should the information be transmitted more widely to authorities, sponsors, and ethics committees? And should the current "one-size-fits-all" approach of the legislation be replaced by a risk-based approach? 

Overall, EFGCP asked respondents to indicate whether they agreed that urgent action was needed to revise the system. All of this raises other interesting questions. If the legislation is not fit for purpose, why is it taking so long to pull together any consensus on the need for change? Does this tell us more about the slowness of the EU legislative system, or about the patience—not to say passivity—of the European clinical trials community? 

Meanwhile, some of the EU countries are fighting back against the risk of losing clinical trials business—risks that arise in part from the regulatory constraints in the European directive now under so much fire, and in part from changes in the broader commercial and scientific context. 

Belgium took advantage of "international clinical trials day" on May 20 (which is just as well, because this columnist would not have known such a day even existed) to issue a warning call that its leadership as a trial center was under threat. "The shift of trials towards emerging countries could change the situation and have grave consequences on the knowledge economy, research and development, and on companies in our country," said a coalition of industrialists, physicians, and the clinical trial community. 

Claiming a top position in trials (with 9% of European trials conducted in Belgium), it vaunted its "dense and dynamic" network of scientists, hospitals, industry, and innovators as the perfect setting for early-stage trials. But, it cautioned, lower costs in India and China are luring large-scale trials, and even Eastern Europe is tripling its grip on the market. 

This is the background to the "Initiative to Promote Clinical Trials in Belgium," which brings together doctors, patient associations, and hospitals to tell prospective subjects about trials, and encourage them to take part. That way, it says, they can get earlier treatment and play a vital role in society. "Clinical trials not only help health; they also boost the knowledge economy and employment in our country." 

To boost the country's attractions, Belgium is promoting electronic submission of applications, rapid trial authorization, simplified administration, cheaper procedures, trained staff, and more efficient subject enrollment. 

Also fresh off the agency design table is a concept paper on upgrading guidance on clinical investigation of medicinal products for the treatment of cardiac failure. It says that emerging data from recent clinical trials have shown the determinant role of the patient clinical profile at presentation on the outcome of the studies, in particular the key role of systolic blood pressure and renal function. A more selected enrollment of patients should therefore be examined, it concludes. 

To better detect an improvement of clinical symptoms or demonstrate a clinical benefit, new composite trial end-points have emerged that are particularly challenging for regulatory decisions. More clarity is needed on the applicability of these composite end-points for regulatory purposes. Commendably, the document notes that "It is not totally clear whether at present unequivocally feasible and scientifically sound proposals can be made to address the major problems identified. Consequently, prior to drafting revised regulatory recommendations it seems prudent to initiate discussion with experts from academia to exchange views..." 

If only the EU had done that with the Clinical Trials Directive. 

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

View from Brussels

The verdict is awaited on the much criticized and long anticipated European clinical trials directive.

Good, Bad or Indifferent?

Pharmaceutical executives readily acknowledge that their industry faces a number of broad challenges, not the least of which are the escalating costs of developing new drugs and a weak public image.

  Both issues intersect in one area of drug development: clinical grants. Based upon an industry survey of people working in clinical operations, and an analysis of grant payments from the perspective of standard of care (SOC), this article argues that cost management and fair market value can be far more effectively addressed than has been the practice to date. 

Clinical grants represent a major and growing cost of developing new drugs. These rapidly increasing costs have been extensively documented and analyzed,

  and the research suggests that clinical trials are the largest single area of R&D operating expenses, with clinical investigator grants representing the bulk of these costs. Many drug development managers appreciate the need to control clinical trial costs. One important, if underappreciated, approach involves avoiding double payments for activities that would be normally covered by third-party payers (including Medicare and Medicaid in the United States) as part of the standard care that any patient would receive at that clinical research site, whether or not that patient is part of a clinical trial. While sites are ethically prohibited from enrolling a patient in a clinical trial if that patient would not otherwise be treated for the illness being studied, many of these patients would be partially covered by third-party payers as part of the standard of medical care.  

Understanding the standard of medical care, however, can be particularly difficult when studies involve multiple countries. At one end of the health continuum some countries are moving toward national medical treatment protocols—the UK's National Health Service is one example. While health care in many countries has one dominant payer, few countries have just one agency delivering almost all their health care, as is the case in the UK. In sharp contrast, the United States has multiple payers and health care delivery organizations. Such differences challenge clinical development teams as they seek to establish medical standard of care guidelines for clinical trial grant payments. In the United States, however, it is easier to establish what constitutes standard of care through the payment practices of third-party payers. 

A second pharmaceutical industry challenge is the changing relationship with physicians. After intense scrutiny from both within and outside the industry, pharmaceutical companies have now developed more stringent guidelines about what they can give to prescribing doctors. For instance, new guidelines prohibit gifts of any sort, restrict meals to those associated with actual medical education, and prohibit industry employees from giving any other objects to medical professionals.   

Some pharmaceutical industry observers are also concerned about the financial relationship between investigators participating in clinical trials and the companies sponsoring the trials. These observers have questioned whether the grant amount for a clinical trial reflects payment only for work performed or whether the payment might be an attempt to influence investigator behavior. In these instances, the foremost concern is whether investigators are being paid at fair market rates or at inflated rates that might influence their behavior.

  While some published research links relative grant payment levels with subsequent investigator prescribing behavior, either of the study drug or all of the sponsor company's drugs, it is obvious that any payment may influence behavior. According to Morin, the number of physician investigators increased dramatically in the last decade as most research moved from institution-based settings to practitioners' facilities, where less stringent ethical standards may prevail. An AMA-adopted Report on the Council on Ethical and Judicial Affairs suggests that some payments to investigators may exceed the fair market value for services performed, and may influence behavior.

In response to the perception of impropriety in these relationships, the industry has made transparent—through 

—the sites involved in clinical trials. In anticipation of the upcoming act requiring pharmaceutical companies to make public the total amounts paid to individual physicians for any type of work, most companies have already begun that process. 

To address the fair market rate issue in clinical trials, companies often benchmark their payments against industry practices.

  The issue of fair market rates is of immense concern to those engaged in managing clinical studies; they recognize that there should be no appearance of paying above market rates by the possibility of double paying for medical activities that would be covered by normal standard of care (SOC) payments. 

 The University of the Sciences in Philadelphia (USP) and TTC, llc, have been conducting an extensive analysis of why some clinical trials finish faster than others, with a number of the findings already published.

Study and site attributes associated with clinical trial studies that complete their work faster

Survey reveals industry practices surrounding standard of care and insurance claims data.

Applied Clinical Trials-07-01-2010

Applied Clinical Trials Digital Edition - July 2010, Supplement

Applied Clinical Trials Digital Edition - July 2010

Osteoporosis Clinical Trials, Not for the Faint-Hearted

Global Trials Get Personal

Act cover

Do Sites Prefer a Sponsor Company or CRO to Run Their Clinical Trial?

Trials in Latin America

Business and News Update July 2010

Good, Bad or Indifferent?

Standard of Care in Clinical Study Budgeting

Biosimilars Make Headway

Transparency Efforts to Reshape Research

Engaging Pharmacists in Research Education

CTMS Can Provide Business Intelligence for Sites