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Asia Pacific and US physicians' attitudes toward involvement in clinical trials.
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.1 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.2, 3 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.4 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.
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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.
Questionnaire. 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.5
Sample. The study sample consisted of all the valid Asia Pacific names and addresses available in the BMIS and ClinicalTrials.gov 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 ClinicalTrials.gov. 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).6
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 ClinicalTrials.gov. Infectious diseases are the most overrepresented in the survey sample when compared to the ClinicalTrials.gov data. It should be kept in mind that the survey respondents could indicate more than one therapeutic area in contrast to ClinicalTrials.gov where the therapeutic categories were mutually exclusive.
Statistics. 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.
Results. 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.
Clinical trial motivation. 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 analysis7 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).7, 8
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.
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.9
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.10, 11 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.12 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.13, 14 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.
Asia Pacific sites currently represent a relatively small but growing number of active sites. Asia also represents a particularly attractive growth market for pharmaceutical products. With a population in the billions, the demand for prescription drugs in these countries will only increase the need to conduct clinical research in these geographies. Understanding the motivation of Asia Pacific investigators should be valuable in helping pharmaceutical companies develop and execute their clinical trial strategies and tactics. It will also be invaluable in assuring the adoption of new drugs by relevant patient populations in the Asia Pacific region.
Harold E. Glass, PhD, is Research Professor of Health Policy at the University of the Sciences in Philadelphia, PA; Visiting Professor King's College, London; and President of TTC, LLC., e-mail: email@example.com. Jesse M. Glass is a PhD candidate at Temple University, Philadelphia, PA, and Senior Associate at TTC, LLC.
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5. TTC, LLC., "Asian and Pacific Principal Investigator Survey Results, Philadelphia," (2009), http://ttc-llc.com/LinkClick.aspx?fileticket=LW4I9QyQm7Y%3d&tabid=82&mid=408.
6. A. Daniel, "English in India," http://adaniel.tripod.com/Languages3.htm.
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10. M. Corrigan, H. Glass, "Physician Participation in Clinical Studies and Subsequent Prescribing of New Drugs," Pharmacy and Therapeutics, 30 (1) 60-66 (2005).
11. H. Glass and B. Rosenthal, "Post-Launch Clinical Investigator Drug Prescribing in the US: The Behavior of Clinical Trial Investigators after Participating in Phase III Clinical Trials," International Journal of Pharmaceutical Medicine, 19 (2) 97-104 (2005).
12. D. Chauhan, "Factors Affecting the Uptake of New Medicines in Secondary Care—A Literature Review," Journal of Clinical Pharmacy and Therapeutics, 33 (4) 339-348 (2008).
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14. H. Glass and R. Kane, "Why Investigators Take Part in Clinical Trials." Applied Clinical Trials, 9 (6) 46-54 (2000).