On a recent trip to the Far East, still a world away from the West, I found myself perplexed, as usual, trying to read the signs. Of course, the hotels, airports, subways, and ATMs make it easy for us English-speakers, but it's not always so easy communicating with a taxi driver, merchant, or a man on the street. English is still far less ubiquitous than we expect in much of the Orient.  

And this also holds for clinical research. While English still reigns as the predominant language of research, it may not be so well understood by those who participate in the research process outside the English-speaking world—coordinators, data managers, clinical monitors, physicians, and patients. While many non-English speakers are eager to do clinical studies, and hungry to learn more of the methods, standards, and processes we've developed over the years in the West, they often need translations of documents, forms, and software before they can really make use of our knowledge. People in the East are especially curious about what's going on with the FDA, since the United States is still the most important market for pharmaceuticals. What's impressive—despite the effort of translation—is how open-minded and enthusiastic they are about pushing the envelope (rather than suspiciously risk averse). 

While there's interest in how the old world is doing, there's a keen recognition of the opportunities offered by the steady migration of clinical studies from developed Western countries toward the developing world, as more and more trials are being conducted in China, Korea, India, and other high-growth economies. The idea of transformational initiatives in clinical research doesn't sound quite so radical to these newcomers—rather, the attitude seems to be "why wouldn't we try something different, especially since we're starting out with a clean slate?" 

Meanwhile, in the Western world, we are investing in many exploratory initiatives intended to transform the research process. And yet, despite these ongoing efforts, we still find the costs of research rising unchecked, while the time it takes to bring a promising new drug compound to market still takes more than a decade and over a billion dollars. At a recent FDA public hearing, Doug Peddicord, Executive Director of ACRO, questioned whether the pharmaceutical industry could really tolerate too many more transformational initiatives: "Every effort at innovation that the FDA supports, directly or through the funding of public-private collaborations, should be measured against three objectives: does it make the drug development process faster, cheaper, or more productive." 

When we talk about transformational initiatives, we think of things such as incorporating more regulatory science, predictive analytics, or adaptive designs into protocols. Or we look at assessing the viability of protocol eligibility criteria against patient databases to ensure we can find patients to shorten enrollment periods. Or we look at productivity improvements through technologies or remote monitoring as companies try to do more with fewer people and try to control escalating trial costs. Many other initiatives are based on secondary use of healthcare and administrative claims data—for exploration of safety signals or epidemiological research—or even to feed clinical research data collection. These ideas have been explored for many years, and can hardly be considered as truly transformational anymore, especially since so many have struggled to achieve traction or, when they do, provide a significant and repeatable return on investment. 

Meanwhile, as we continue to try to make healthcare information more electronic and exchangeable, we still can't quite seem to make it very interoperable between patient care and research. This is due to more than the challenge of integrating technologies—the primary problem is really one of semantics. While healthcare and research both want to improve patient treatment, we just can't seem to speak the same language. 

There are many excuses for this. The typical way that researchers devise protocols is based on identifying what data they want to observe and which endpoints to measure, yet they don't define these in the same languages as healthcare IT. And it's not just a matter of translation—it's also a question of data reliability. Epidemiologists are well aware of the limitations involved in secondary uses of healthcare information, which is grounded in the assignment of billable diagnoses for reimbursement purposes, a consequence of the United States' fee for services healthcare system. As a result, much of what's in an electronic healthcare record is more likely to be driven by reimbursement than data quality or accuracy. Then there are the coding system variations, such as our use of MedDRA to code adverse events for clinical studies, even though MedDRA is never used in healthcare to describe problems or diagnoses. 

And yet even data that should flow smoothly between systems—such as laboratory results and vital signs—tends to get stuck along the way. Healthcare systems, for instance, typically use LOINC codes to represent lab tests and their attributes—which research systems prefer to spell out as a set of variables in a dataset instead.  

The disconnect that exists between basic science, patient care, and clinical research has been aptly described by Chris Chute as the "chasm of semantic despair." Chris is referring primarily to the botched hand-offs in translational medicine, but it applies equally to the gap between healthcare and research information systems. 

Thus, in healthcare, a lot can be lost in the flow of information between patient, physician, institution, reimburser, and researcher. In such information exchanges, the parties may think they're talking about the same thing, but often they're not. It's like the child's game of telephone—also known as "Chinese whispers"—something always gets lost along the way. It's particularly perplexing when we use the same terms with variable meanings depending on different contexts, dependencies, or parameters. The problem is that we can't always tell when we're talking about concepts that are exactly the same, or merely similar, or not alike at all despite appearances to the contrary. This is sometimes caused by conflicting assumptions, but more often simply a result of using terms with imprecise meanings that have not been explicitly and unambiguously defined. And rather than spend the time to look for common concepts between these parallel but conflicting worlds, it's easier for a scientist to just describe in plain English what he wants just this time. Over and over again. 

Asia makes one appreciate the need for coded data, which makes translation so much easier. Even when we do use common terminologies in research we feel a need to create our own lexicon rather than build on systems already in place. For example, why don't we use LOINC more in research? Now that the National Library of Medicine is defining quality measures in LOINC to support the assessment of meaningful use related to implementation of EHR systems, including questions like those in the FACIT quality of life questionnaires for chronic disease sufferers, isn't there an opportunity to represent research questions there as well? Especially when some of these quality measures look quite similar to efficacy measurements for clinical protocols, and could become fundamental objects of comparison for comparative effectiveness research—if we only used the same language. 

Moreover, as research data standards for disease areas are developed, they will be specifying clinical data elements in trials that will often parallel or overlap quality measures and value sets in healthcare.  

Of course, learning to speak and read in other languages is difficult. But the lesson is clear—we need to clearly define the clinical observations and endpoints we use during research and equate those with any observations used in healthcare, and represent them, wherever possible, as coded data elements. The use of coded data not only ensures that we can pool and compare data elements for multiple primary and secondary purposes, but it also makes it possible to more easily internationalize our data. It's not practical to translate endless documents into multiple languages over and over for each study, but it's entirely possible to represent the definitions and descriptions of a coded data element in other languages and character sets, so the meaning of those codes can be instantly rendered in the language of the reader. This is a classic "do once, use many times" scenario that enables the universality of language used in healthcare and medical research.  

And this is a way to sensibly expand clinical research to China, Korea, and other developing geographic areas which will bring new patients to research studies in coming years. 

Coincidentally, this also helps cross the chasm between the world of healthcare and that of research. Rather than describe the research concepts, measures, and endpoints we wish to observe merely in prose, we need to record these as coded, structured data. As much as possible we should try to use the same terminologies—or at least have consistent mapping between them. Of course we have to deal with the vast universe of vocabularies already in place, but the relationships between these concepts can be represented in systems, such as through the power of the semantic web. But we need to stop creating new languages as we go along, and learn to build more on what's already in place.  

This is an essential foundational requirement of a learning healthcare system that can operate as a true ecosystem between scientific research, clinical research, and patient care—from bench to bedside and back. So, it's about time we all started getting on the same page. 

is Chief Technology Officer for the Clinical Data Interchange Standards Consortium (CDISC). He resides near Chicago, IL, and can be reached at 

Articles

CTI Insights

To really transform global research we need to agree on a common language.

Transformation and Translation

(Research Triangle Park, NC) a pharmacovigilance services provider, has announced the addition of industry veteran 

 MBA, RAC, as Chief Compliance Officer. In his new role, Pierce will oversee DSA's Quality and Regulatory Compliance and Risk Management teams. Pierce has more than 35 years of government and industry experience in regulatory and quality compliance.  

 has joined the executive management team as Chief Commercial Officer. Engelhart will be responsible for leading business development, proposals and contracts, marketing, and sales activities worldwide. Prior to joining ACM Global, Engelhart was Chief Commercial Officer at Cryoport, Inc. a provider of leading-edge cold chain logistics services.  

 (Dublin, Ireland)has made two senior appointments in Early Phase and Epidemiology & Risk Management departments. 

MD, has joined ICON as Senior Clinical Research Physician at the Clinical Pharmacology Unit in Manchester, UK. Leung joins the company with over 23 years of hospital and pharmaceutical industry experience in a variety of medical specialties including diabetes, endocrinology, and general medicine. 

 has been appointed Director, Epidemiology and Risk Management Practice, ICON Late Phase & Outcomes Research. Anton has over 25 years of experience leading international epidemiologic, health economic, and outcomes research, and other market access initiatives.  

 (Cincinnati, OH), an end-to-end drug development service provider specializing in the 505(b)(2) process, has appointed 

 as Vice President of Drug Development. Barnette will be responsible for the growth of the company and excellent customer service utilizing his experience within the drug development industry and his knowledge of FDA regulations. He will be stationed in the Durham, NC office.  

 (Lyon, France) as Vice President, Clinical Operations for REGISTRAT-MAPI EU. Working as a key member of the organization's executive leadership, Doize will assume responsibilities for clinical operations in Europe and affiliated territories. She will be responsible for the strategic development and functioning of international operations to ensure that growth, profitability, quality, and customer service goals are achieved.  

 (Verona, Italy), an international full-service CRO has acquired 

an established international CRO with offices in the United States (Cambridge,MA) and the United Kingdom (Stirling, Scotland). Pleiad was launched in 1999, supporting clients in multiple therapy areas and with dedicated medical device and ophthalmology divisions. Additionally, Pleiad also possesses strong capabilities within statistics and data management.

(Wilmington, NC) has funded the strategic merger of

 creating an organization designed to accelerate clinical trial enrollment from beginning to end: Inclinix-PMG Holdings, Inc. The company will be led by 

 CFO. The company will operate in the short term as two divisions.

(Rockford, IL), a pharmaceutical, clinical, and commercial contract packager in the United States, and 

(Hey-On-Wye, UK), a leading supplier of pharmaceutical commercial packaging and clinical supply services in the United Kingdom, are further aligning their businesses to become a global end-to-end pharmaceutical packaging company. AndersonBrecon will feature 12 facilities across two continents, and more than 1,500 dedicated associates who will work to provide medications to patients in more than 100 countries around the world. 

 (King of Prussia, PA), a provider of payment technologies for the clinical trials industry, has been awarded the Philadelphia Alliance for Capital and Technologies Enterprise Award in the Technology Startup Division. Greenphire and other Enterprise Award winners and finalists were recognized at the 19th Annual Enterprise Awards gala in front of 1,200 prominent business leaders in May in Philadelphia. The Enterprise Awards honor exceptional technology and life sciences companies and entrepreneurs in the greater Philadelphia region each year.

(Horsham, PA), a provider of eSource solutions for clinical trials, was named to the Gartner's prestigious 2012 Cool Vendor List for life sciences. Gartner cited the potential to eliminate errors, cut costs, reduce timelines, and simplify clinical trial processes as reasons to include Clinical Ink this year. Clinical Ink is the only company on the list to focus exclusively on clinical operations. 

 (Princeton, NJ), inVentiv Health's clinical segment, and a leading provider of clinical development services to pharmaceutical, biotechnology, generic drug, and medical device companies has been named the recipient of the US Chinese Anti-Cancer Association (USCACA) Distinguished Partner Award for its support of oncology clinical trials and cancer research in China. USCACA is a non-profit organization that facilitates collaborations among cancer researchers and physicians in the United States and China. 

(New York, NY), a provider of eClinical technologies to the life sciences industry, announced that 

(Raleigh, NC), a therapeutically focused CRO, has selected Trial Interactive as its global electronic trial master file solution. Trial Interactive is a secure, web-based platform that reduces the redundancies inherent in paper-based TMF management. Trial Interactive's interface is available in more than 20 languages, which will enable INC Research to deploy the solution in the local language of the end user.

The Ethical Standards in Health and Life Sciences Group

 (London, UK)has published a new series of Clinical Trial Transparency Principles and Facts. This is the first time that leading healthcare professional bodies and senior representatives of the pharmaceutical industry have agreed to a joint approach on this issue. This is a step forward in the ongoing move across the entire research community to drive best practice in clinical research reporting.

 (New York, NY), an early phase and specialty CRO that provides clinical drug development services to the pharmaceutical industry, has opened a second Phase I unit in Southern New Jersey. The 50-bed capacity, 15,000 square foot specialty pharma Phase I unit features semi-private rooms, a large PK sampling facility, a bioanalytic laboratory, pharmacy, and exam rooms.

CTI Clinical Trial and Consulting Services

 (Cincinnati, OH) has announced the formation of a new, wholly-owned French subsidiary, CTI Clinical Trial and Consulting Services SARL, and the opening of an office in Paris, France. The new location continues the company's expansion throughout Western Europe. CTI has been working for more than a decade in the drug development industry in North America, Europe, and South America, specializing in clinical research programs involving critically ill patient populations. 

 (Raleigh, NC), a leading clinical research organization, announced the expansion of operations in the Netherlands and the United Kingdom to accommodate staff growth and strong client demand for Phase IIa-IIIb service offerings. Located in the thriving city of Utrecht, NL, the new Dutch facility will host 20-plus employees and is the first PRA office in that region to primarily support product registration trials.

 (Riom, France), a CRO that provides fine chemistry services, has moved into new premises in Riom, near Clermont-Ferrand, in the Auvergne region. The move will strengthen Roowin's position as one of the few companies in France that offers a comprehensive range of services, from early-stage research to the production of GMP batches for Phase I and II clinical trials.

(Evanston, IL), a digital services provider to the global biopharma industry, has released a new generation of eClinical technologies for mobile devices. The new mobile-friendly platforms deployed by MedPoint include: TriPort Clinical Trial Portal, a secure, fully validated technology that delivers study-specific information, training, and communications; TelePoint Virtual Meeting System, which simultaneously connects participants from desktop computers, smartphones, and tablets; ActivMedia Modules, which engages users for self-learning, real-world simulations, and training certification; SFX Site Feasibility Xelerator, can complete survey forms over mobile devices.

In the July news section, the article "Managing Budgets in Complex Times with Tight Variances" was published with inaccuracies. Please visit 

www.appliedclinicaltrialsonline.com/budgets

Business News

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

Business and News Update August 2012

 Going With the Flow of Health Care Research

 Patient Recruitment and Retention are Major Challenges for Clinical Trials in CNS

Pharmaceutical companies have in recent years increased the number of clinical trial sites in areas outside Europe and North America. Driven by the need to find relevant patient populations and manage clinical trial costs, clinical development organizations in sponsor pharmaceutical companies and contract research organizations (CROs) have looked to these new geographies to supplement, and in some cases, replace clinical site work in the more established geographies of North America and Western Europe.

  Clinical site growth in the Asia Pacific region for example has exceeded the global rate, increasing by an average of 20% over the last two years compared to a decrease in the rest of the world.

  While industry magazines may contain articles about various aspects of conducting clinical trials in these new geographies, there has been little research on the investigators themselves. For example, why do they take part in clinical trials? What do they hope to get out of this participation? And, what do they find especially challenging in conducting clinical research?  

The University of the Sciences in Philadelphia and TTC, LLC have been conducting a long-term, multi-national study on why some clinical trials finish faster than others. This multi-year research effort includes a global survey of clinical investigators. Earlier research efforts presented US and Latin American data.

  This article examines investigator related data from the Asia Pacific region, including: site profiles, investigators' reasons for taking part in clinical research, as well as what these physicians find especially difficult about conducting clinical research. The results are compared to previously published results for US investigators.  

Asia Pacific investigators generally have less clinical development experience than US investigators, and are more likely to work in medical institutions rather than in private practice. Investigators from both regions share a strong desire to contribute to the creation of medical innovation through their participation in clinical trials. However, US investigators are relatively more motivated by financial considerations than are Asia Pacific investigators. Both groups of researchers are generally frustrated by the same obstacles faced during the conduct of clinical trials.  

The questionnaire contained several basic areas: a description of the site including its staffing, clinical trial experience, and capabilities; the investigator's possible reasons for taking part in clinical research; the potential aspects of clinical trial conduct that are the more frustrating; plus investigator evaluations of leading pharmaceutical companies and CROs. Following a pretest of the instrument, the Asia Pacific data collection was completed in 2010.  

The questionnaire included a list of 12 potential reasons for why an investigator might participate in a specific clinical trial. Respondents were asked on a scale of 1-10, with 10 being very important and 1 not important at all, how significant each of the 12 reasons would be for their participation in a Phase III clinical trial of a new compound being tested by a pharmaceutical company. To eliminate potential response bias due to the order of the questions, we systematically rotated these items in five versions of the questionnaire. A copy of the complete questionnaire can be found at the study website. In addition, the website provides the total set of Asia Pacific respondent answers to the questions on that questionnaire.

The study sample consisted of all the valid Asia Pacific names and addresses available in the BMIS and 

 databases. Each site was sent a mail questionnaire. Two mailings were conducted, followed up by a web-based survey of the non-responsive sites, for a total response rate of 21%. The questionnaire was in English for all the Asia Pacific countries. Japanese data are excluded from this analysis and will be published in subsequent research.  

As with any voluntary mail and web-based questionnaire, there is the potential for an appreciable skew in the responses. Those responding may differ significantly, in important aspects, from those not responding. There is an approximate balance between the size of countries in terms of active clinical sites and the number of survey respondents from that country. The three largest countries constitute 75% of survey respondents and 63% of sites in 

. India is somewhat overrepresented, with China slightly underrepresented. The questionnaire was in English, and in general there is an overrepresentation of respondents from countries where English was an integral part of the medical community (Table 1).

Table 1. There was an over representation of respondents from countries where English is an integral part of the medical community. 

Respondents indicated all the therapeutic areas in which they felt capable of conducting clinical research (Table 2). The data in Table 2 does not indicate any noticeable under-representation in the survey data of the therapeutic areas in which companies are currently working in the Asia Pacific area. In most cases, a higher percentage of sites indicate feeling qualified to work in a particular therapeutic area than is required to meet the demand for current clinical trial activity in the Asia Pacific region.  

Table 2. In most cases, a higher percentage of sites indicate feeling qualified to work in a particular therapeutic area than is required. 

Oncology, cardiovascular, and endocrine and metabolic were the three most frequently mentioned. The remaining therapeutic areas more or less parallel the data found in 

. Infectious diseases are the most overrepresented in the survey sample when compared to the 

 data. It should be kept in mind that the survey respondents could indicate more than one therapeutic area in contrast to 

 where the therapeutic categories were mutually exclusive. 

Analysis of variance was used when differences of means were being tested. Categorical variable differences were tested using chi square analyses and gamma approximate significance measures. All analyses were conducted using SPSS version 18. 

 Investigators in the Asia Pacific area more often work at academic medical centers or hospitals, in contrast to their US counterparts where a distinctly higher percentage of clinical investigators are in private practice. About the same percentage of Asia Pacific investigators though are located in dedicated clinical research sites as is found in the United States. A third (32%) of US clinical research investigators are located at sites dedicated to clinical research, while the comparable figure for Asia Pacific is 27%.   

Table 3. The majority of US sites are office based, while Asia Pacific trends toward academic-based investigator sites.  

On average, Asia Pacific sites have a greater number of full-time equivalent study coordinators than do the US sites. Across all global regions, academic medical centers and hospitals often tend to have more study coordinators per site (Table 3). Relatively more Asia Pacific investigators work in these types of organizations, with their generally higher staffing levels. Asia Pacific sites though have, on average, done appreciably fewer Phase II-IV clinical trials. Consequently, in many instances Asia Pacific site personnel manage distinctly fewer clinical studies than do their US counterparts (Table 4).  

Table 4. Asia Pacific site personnel manage distinctly fewer clinical studies than do their US counterparts. 

Factor analysis was used on the 12 item list of questions used to establish investigator motivation for participation in clinical trials. The analysis revealed three dimensions why investigators take part in clinical research: a desire to take part in medical innovation; financial remuneration; and study or sponsor items specific to a given clinical trial. Factor analysis is a widely used and validated technique that explores whether there are underlying dimensions, or factors, which might explain a pattern to the responses to each of the individual items in a set of related questions. The technique originated in psychometrics but is now widely used in operations research, marketing research, economics, and survey-based research in general. While answers to individual items are, at times, just answers to individual items, responses to individual items may also be the result of a latent pattern, such that answers to an individual item are tied to the pattern of responses to the other items. Factor analysis

  then provides the study with a perceptual map of the various reasons why an investigator might take part in a specific clinical trial. We report the answers to each of the items by the factor analysis dimension to which they are linked, comparing the results to the US investigator data.  

Four items in the factor analysis were related to each other through the underlying common dimension of medical innovation. There is a generally similar response pattern to the individual items for the investigators from both geographic areas. For instance for both Asian Pacific and US investigators, the opportunity to work on a potentially new therapeutic option is the single most frequently mentioned individual reason for their participation in a clinical trial. The two investigator groups do differ on one item. A significantly higher portion of Asia Pacific investigators think that the prospect of interacting with other physicians taking part in the clinical trial is very important (Table 5).

Table 5. Compared to their US counterparts, Asia Pacific investigators think that the prospect of interacting with other physicians taking part in the trial is very important. 

Throughout the analysis it was examined whether differences existed between key subsets of the Asia Pacific sample. There were enough investigators from two areas in particular, Australia/New Zealand and India to enable us to see if investigators in these sub-geographies differed from investigators in the other parts of Asia. While both sub-geographies are on the opposite boundaries of the Asia Pacific region, both areas have stronger traditions of British medicine than is the case of many of the other Asia Pacific countries. For reasons of sample size and medical we compared the responses to each item for the Australian/New Zealand, Indian investigators to the investigators from other Asia Pacific countries. For each item we constructed an analysis of variance tool, using geography as a fixed factor along with two covariates, the total number of Phase I-IV studies conducted by the site within the last three years, and the percentage of all studies conducted by that site over the last three years that were managed by CROs. By incorporating the covariates, we wished to eliminate any differences that might be due to the different levels of clinical trial experience across the sites within the various sub-geographies. In this way we wanted to isolate the impact of the geography alone. Across the four individual items used in this portion of the analysis, there was a significant difference across the sub-geographies on only one item. Indian investigators, along with those from the other Asian countries, valued the opportunity to interact with the other investigators in the study more than did investigators in Australia and New Zealand. The set of significant models can be found at 

http://physicansandclinicaltrials.webs.com

The second factor covers items relating to financial considerations. Noteworthy is how much more importance both US and Asian investigators generally place on many of the individual items in medical innovation than is the case with the financially related questions. Even taking into account that participants could have been partially motivated to the desire to provide socially acceptable answers, the differences are still clear. Financial considerations are less important than is medical innovation for both US and Asia Pacific investigators. However, financial issues are even less important for many investigators in the Asia Pacific region.  

Analyses of the sub-geographies revealed two statistically significant differences between investigators from India, Australia/New Zealand, and the remaining investigators from the other Asia Pacific countries. Investigator across all the Asia Pacific sub-geographies place less value on financial considerations than do US investigators (Table 6). Australian/New Zealand are distinctly less likely than other Asian Pacific investigators to emphasize the prospect of additional studies and the amount of up-front study start-up money as reasons for conducting clinical research.  

Table 6. Investigator across all the Asia Pacific sub-geographies place less value on financial considerations than do US investigators. 

Sponsor and study-specific considerations

There are no significant differences between US and Asia Pacific investigators for the individual items in this factor (Table 7). The indication being studied in the clinical trial is an important reason for all investigators. At the bottom of the importance list for both groups of investigators are two items: whether a CRO or sponsor company runs the study, and whether or not the sponsor company is a major pharmaceutical company.  

Table 7. US and Asia Pacific sites scored very closely in their responses to sponsor and study specific considerations questions.  

Statistically significant differences existed by sub-geography for all five items in this dimensions. Investigators from Australia/New Zealand placed less importance on sponsor considerations than did their counterparts in the rest of the Asia Pacific area.  

Dissatisfaction with the conduct of clinical trials. 

The investigators also indicated a number of areas relating to the conduct of clinical trials that were particularly troublesome. The general response profile of the Asia Pacific investigators approximates the US pattern. For both sets of investigators, the mechanics of study finance were first on their list of troublesome study conduct challenges. Forecasting the study budget is rather more of a challenge for the Asia Pacific investigators. Perhaps this may be partially a function of the lower experience level of many Asia Pacific sites. There is a large minority of Asia Pacific sites who are concerned about their ability to forecast, track, and collect their costs (Table 8).  

Table 8. A large number of Asia Pacific sites are concerned about their ability to forecast, track, and collect their costs. 

 The most striking difference between Asian and US investigators relates to adverse event reporting. US investigators are visibly more concerned about this issue. The area of drug safety has received extensive professional and mass media attention over the last few years in the United States.

Asia Pacific currently represents a relatively small, but growing share of active clinical sites. Few of these sites are in private practice, in contrast to the United States. Given the relative newness of the Asia Pacific region as a place in which to conduct clinical trials, it is not surprising that the sites in the study have less clinical trial experience. Despite differences in clinical trial experience, Asia Pacific investigators share with US investigators an over-arching desire to take part in the creation and dissemination of medical innovation.  

Clinical trials are especially valuable vehicles that enable investigators to share with, and learn from, other physicians focused on cutting edge medical activities. As one hospital-based investigator wrote: "Clinical trials are certainly an important way for me to learn the latest in medical thinking and practice. I can learn from my colleagues here and from (North) America and Europe." Similarly, another investigator indicated: "My participation in clinical trials is a way for me to learn from others and in turn share with the other physicians in my daily practice."  

Understanding investigator motivation in Asia Pacific can have a number of important additional benefits, including product success for pharmaceutical companies conducting or sponsoring clinical trials in Asia Pacific. In the United States individual physician prescribing data are available for commercial and research purposes. Although Phase III trials are usually double, or even triple blinded, US investigators often prescribe more of the study drug when it comes to market if they have participated in the clinical trial. This is particularly true if the compound is a first in class one.

  The number of incremental prescriptions written by clinical investigators is hardly critical to the successful launch of new products, yet what investigators say about the drug to other physicians may be important. Research has demonstrated that the primary reason a US physician prescribes a new drug for the first time is what a valued peer may have said about that drug.

  Pharmaceutical sales representatives may bring a drug to a physician's attention, but what other valued physicians say about that drug frequently carries the most weight in that physician's decision to prescribe the drug for the first time. The same new drug adoption dynamic found in US investigators may well be at work among Asia Pacific physicians taking part in clinical trial research.  

Investigator motivation can have important clinical trial study conduct implications as well. Investigators in Europe and North America indicate a willingness to accept a lower cost per patient clinical grant in order to work on a novel compound. An analysis of grant payment levels and compound novelty indicates this is empirically the case in the United States.

  Given the importance that Asia Pacific investigators place on the desire to participate in medical innovation, clinical trial managers should consider this factor in the final cost per patient grant payment levels they negotiate with their sites. Especially attractive new compounds may not require the same grant payment levels for a site to participate in that compound's clinical trials. 

Asia Pacific and US investigators do not seem to differ widely in what disturbs them about taking part in clinical research. The especially high visibility of several drug safety related product recalls in the US, along with the major reorganization of the FDA around drug safety may also help explain the higher discomfort US investigators express with SAE reporting. 

Pharmaceutical companies may additionally be more effective in recruiting and managing Asia Pacific sites if the sponsor company, or CRO, takes the time to share the results of the studies with the investigators. Clinical sites will not work for unrealistically low payment levels. However, the intensity of their participation in a specific trial, and willingness to work on future studies with a given sponsor company or CRO may increase if the sites feel that they are more fully partners in the clinical trial. Understanding the outcome of the research is a potentially promising way to increase that sense of partnership. This added effort on the part of sponsor companies and CROs may ultimately result in better clinical trial performance as well as faster adoption of the study compound if, and when, it comes to market in the respective Asia Pacific country.  

Asia Pacific investigators are markedly more motivated than their US counterparts by the prospect of interacting with other physicians during the study. Pharmaceutical companies and CROs may increase a sense of partnership with sites, if the organization managing the clinical trials maximizes the level the opportunity for Asia Pacific investigators to learn from, and share with, other relevant physicians. 

Feature Article

Asia Pacific and US physicians' attitudes toward involvement in clinical trials.

Physicians' Outlook on Participation

ACT Cover

Quality is often hard to define and "awareness" according to the Wikipedia definition is a "state or ability to perceive, to feel or to be conscious of..." Unsurprisingly, "quality awareness" can be a relative concept that is difficult to understand and that approach should be aimed at both management and employees within a CRO in order to be effective.  

Quality starts from the top of the organization which defines the culture, values, and vision through various mission statements, policies, and plans, filtering down to the employee level. Management needs to really engage with building quality and spread the message to their teams. Employees observe and reflect on the messages and actions that come from their managers. 

Quality is not just a way to gratify sponsors or regulatory authorities, but should be a part of an established and dynamic quality management system (QMS) and incorporated into everyone's daily activities. It is vitally important to establish, actively improve, and continue to develop policies and processes such as standard operating procedures. Although management may be reluctant to lead the way and provide necessary resources, quality assurance (QA) may need to remind them of the costs involved in loss of reputation and business without quality being inherent in daily activities. Often, quality is seen as costly and a distraction from the main business. 

The QA group has a high-profile role within all organizations and should be viewed as partners, reporting to senior management, influencing processes and strategies, and as such their ability to communicate effectively despite all these challenges is at times difficult. QA visibility within the organization, either by local support or using a help desk or just knowing who to go to with questions, encourages reporting of quality problems before they become significant issues. Operational teams should respect the role of quality and respond positively and in a timely manner to QA.  

The role of QA has changed over the last few years with more time spent on "virtual auditing" and remote reviews of data which are both cost effective and efficient. The ability to do "more with less" actually translates into more interactions throughout the organization, which further raises the quality profile.  

All employees need to be respected, nurtured, work with their management teams in defining processes, and made aware of their contribution and their importance in achieving acceptable quality levels. Only by holding the whole organization accountable for working together to focus on quality improvements and metrics to track various quality steps, can quality awareness can be raised.   

Quality should be part of everyone's job by encouraging objectives which look at defining better processes or ways to develop a higher quality product or looking at the amount of positive feedback that is received, rather than negative objectives. 

Staff training and performance are important to running a successful quality project. Roles and responsibilities define accountability and need to be carefully defined. A good place to start is with a clearly defined contract so everyone knows their part. CROs need to find the right balance between speed and quality. Quality is a "given" and many contracts have conflicting goals which distract from quality through use of unrealistic recruitment penalty clauses. A true partnership approach is required and responsiveness needs to be bilateral. 

Raising quality awareness is not just the role of the QA department but it requires buy-in from everyone. 

Vice President, Global Quality Assurance, Premier Research Group E-mail: 

A Closing Thought

Quality is not just a way to gratify sponsors or authorities, but should be part an established and dynamic QMS.

Raising Quality Awareness in CROs

The new clinical trials rules for Europe made their tentative appearance in mid-July. Tentative, because at present they are merely in the form of a proposal from the European Commission: the legislation as such will come into effect only once the European Parliament and the 27 member states have given their views and, probably, imposed some of their own modifications. But the shape of the likely outcome is discernible even at this stage.  

So what does European Health Commissioner John Dalli propose as the escape route from the current rules—which virtually everyone, including Dalli himself, agrees are deeply unsatisfactory? On the surface, his ideas look like an imaginative and even courageous attempt to tackle the inconsistencies and divergences that plague clinical trials—and particularly multi-country trials—in Europe. At the heart of the proposal is a bid for some greater uniformity, through creating a mechanism for a single application for trial authorization, a coordinated European assessment procedure, a single opinion from each of the 27 member states, and—it is hoped—a single decision valid for all the countries concerned by a trial. 

The immediate response from the clinical trials community has been largely favorable—even enthusiastic. But at the same time, questions remain over some aspects of the proposal that will require longer study and greater clarity. 

First, let's take a quick look at what the proposal contains.  

The scope is largely unchanged—covering virtually all pre-authorization clinical research on medicines. The only exception is for non-interventional studies, such as surveys amongst doctors without additional data mining. (Post-authorization safety studies remain governed by the European Union's basic 2001 directive on medicines). 

The major innovation is a new authorization procedure for clinical trials, based on a harmonized authorization dossier, a single submission point (a "portal") for applications, and a faster assessment procedure with a key role for a "reporting member state," and the possibility to extend a trial to additional member states. The portal would be managed by the European Commission and be free of charge for sponsors.  

Clearer—and much shorter timelines—would be established, and the concept of tacit approval would be generally applied. Modifications would require authorization only if they implied "a substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated." And a coordination forum would address conflicting views that might arise among member states in the authorization procedure—although a dissenting member state would be able to opt out of the conclusions reached at EU level on an application. Member states should be allowed to levy fees for processing trial authorization applications, but they should not require multiple payments to different bodies engaged in the assessment. 

The start of the clinical trial, the end of recruitment for the clinical trial, and the end of the clinical trial should be notified. The results should be reported to the competent authorities within one year of the end of the trial. Clinical trial data submitted in support of a clinical trial application should be based only on clinical trials recorded in a publicly accessible database.  

Risk assessment would play a much greater role than under the current rules. How much a trial needs monitoring would vary according to the degree of intervention, the objective and methodology, and how far it deviates from normal clinical practice. The rules on safety reporting would be streamlined. The rules will be made less onerous for medicines used in a clinical trial that are not investigational medicinal products— "auxiliary medicinal products" (or, until now, "non-investigational medicinal products"). "The applicable rules should allow for some flexibility," the proposal recommends. Similarly, "the rules for labelling should be adapted to the risks to subject safety and the reliability and robustness of data generated in a clinical trial." In particular, no additional labelling should be required in open-label trials for investigational or auxiliary products that have already been placed on the market. 

Similarly, insurance obligations would be eased. The commission accepts that the obligatory insurance/indemnity in the current rules has driven up costs and administration without perceptible benefit. So the new rules "acknowledge that clinical trials do not in all cases pose an additional risk to subjects compared to treatment in normal clinical practice." Consequently, where there is no—or negligible—additional risk, it would no longer be necessary to provide specific damage compensation. 

To cover trials that do pose additional risk, the regulation would oblige the sponsor to ensure compensation —through insurance, or through an indemnification mechanism that the new rules would require member states to set up to help non-commercial sponsors overcome difficulties in obtaining coverage for possible compensations.  

Other innovations include the introduction of provisions for clinical trials in emergency situations where urgency makes it impossible to obtain free and informed consent, wider powers for European Commission staff to perform controls and inspections in member states and beyond, and allowance for the concept of co-sponsorship, "since clinical trials are increasingly initiated by loose networks of scientists or scientific institutions" (although "it is clearly preferable to have only one sponsor per clinical trial"). New provisions would make clear that the responsibility of the sponsor is distinct from issues of liability for harm of a patient. "The rules on liability depend on the applicable national liability laws and are independent from the responsibility of a sponsor," says the commission. 

But certain fundamental principles remain unchanged and are clearly reiterated. "The rights, safety, and well-being of the subjects shall prevail over the interests of science and society," says the proposal.  

One of the areas that has provoked questions is how the split will be made between matters dealt with at European level and what will remain under national control. The commission says its aim is to make "a clear distinction between aspects where member states cooperate in the assessment, and aspects of an intrinsic ethical or national/local nature where the assessment is made by each member state individually" (notably, liability, ethical considerations such as informed consent, or local factors such as the suitability of the trial site). The answer proposed is to leave to each member state the definition of "the organizational setup and internal competencies for assessing clinical trial authorizations," subject only to the provision that "international guidelines on the independence of the assessors are observed."  

The permission to conduct a clinical trial should "be contained in one single administrative decision by the member state concerned." The distinction "does not have implications for the body that performs the assessment, nor does it interfere with the member state's internal organization of the bodies involved in decision-making," the proposal says. The new rule would not lay down which body or bodies should make the decision, nor would it regulate or harmonize the precise functioning of ethics committees, nor impose a systematic cooperation at an operational level between ethics committees in the EU. What the commission insists on is only that applications "will have to be assessed jointly by a reasonable number of persons who are independent, who have collectively the necessary qualifications and experience in all relevant fields, including the view of lay persons." 

This formalizes an overlap—not to say a blurring—of responsibilities. As the commission says, "since science and ethics cannot be separated, it does not limit the ethics committee's scope of the assessment to issues which are purely ethical."  

Language use has also prompted some questions. The text says it should be left to each member state to decide what languages it will accept applications in—merely adding that "member states should consider accepting a commonly understood language in the medical field as the language for the documentation not destined to the subject." Although this implies that English should be widely accepted, it would not prevent some countries from imposing other requirements. 

The legal form of the proposal would be a regulation (rather than the rather form of a directive—which is the basis for the current rules). This, the commission points out, ensures that the member states work from an identical text, rather than on diverging national transposition measures, when they make their assessment of a trial authorization application, monitor safety reporting during clinical trials, or labelling of products used in a trial. It also prevents member states from introducing additional procedural requirements. "Clinical trials, including multi-national clinical trials, can be planned and conducted on the basis of one regulatory framework, rather than on the basis of a 'patchwork' of 27 national frameworks." To allow for a smooth transition from the current directive to the new regulation, both sets of rules would apply in parallel for three years. 

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

View from Brussels

Clinical trials community reacts favorably to tentative set of new rules, yet questions remain.

Smart European Solution to Clinical Trials?

This month we focus on the increasing protocol complexity in the past decade, something that has garnered a lot of attention over the past few years. Perhaps not surprisingly, Phase II and Phase III data from the Medidata Insights metrics warehouse show that clinical studies have grown significantly in complexity over the past decade. What caught our eyes was that after the large increase in metrics in the first half of the past decade—and despite continued warnings from experts on the topic—complexity continues on an upward, though admittedly less steep, trend.  

The protocol complexity value—a new addition to the Medidata Insights metrics warehouse—provides a quantifiable, repeatable measure of effort required to conduct a study. The calculation takes the quantity of each trial procedure and clinical research activity conducted per completed patient and multiplies each by a relative value unit (RVU). RVU is a mathematical expression of the site work effort required to conduct each procedure and clinical research activity. Thus, the measure indicates the overall effort required to conduct a study and the associated burden on sites. 

So what's the impact of increased protocol complexity? According to the Tufts Center for the Study of Drug Development, increased execution burden on sites can lead to more costly clinical trials and potentially greater issues with site training and performance ("Assessing the Impact of Protocol Design Changes on Clinical Trial Performance," Tufts CSDD). Additionally, it is estimated that 15% to 30% of data collected during the average clinical trial process is never used in a new drug application. This increase in added complexity without corresponding added value increases direct costs while negatively impacting patient recruitment and retention. This happens as increased procedure frequency and invasiveness negatively impact the patient experience in clinical trials—for example, the screen-to-complete ratio was 52% from 1999 to 2002 and dropped to 28% from 2003 to 2006 ("Trends and Implications of Increasingly Complex Protocol Designs," Tufts CSDD). Screen failure rates are significantly costly for sponsors; we estimate the average cost per failure across the industry to be roughly $1,200. 

Protocol complexity in Phase II/III trials, 2000-2011.			

As shared in previous posts, data from the Insights metrics warehouse indicate that three other key metrics are steadily rising: eCRF complexity, number of on–site monitoring days, and the amount of SDV during each on-site day. A correlation among these measures is a reasonable conclusion and, furthermore, it is a plausible deduction that an increase in protocol complexity is driving an increase in eCRF complexity and design timelines, monitoring costs and the burden on both sites and patients.  

Despite the significant amount of discussion on the increasing complexity of protocols across the industry—and the need to address this situation—the trend continues. Given the pressure to control costs and streamline trials, is there any way clinical R&D organizations can reduce the cost of clinical trials and the burden on sites and patients when protocol complexity continues to increase steadily?  

What is your experience with protocol complexity? Do you find your protocols, or those of your partners, to be more complex? If so, how does increasing complexity impact other aspects of your clinical operations downstream?  

As always, Medidata is interested to hear your take on this result. Please also stay tuned as the company delves further into the Insights metric data through 2012. 

Protocol Complexity

Issue PDF

Sites: Physician's Attitudes Toward Participation 
Also in this issue: 
Europe's Tentative New Rules 
Common Language for Global Research 
Quality Awareness in CROs

Applied Clinical Trials-08-01-2012