Japan is considered to be one such country that differs greatly linguistically and culturally from Western countries. Another reason why major global pharmaceutical companies want to have Japan participate in global clinical trials is sales that can be made in Japan in the pharmaceutical market. The global pharmaceutical market is said to be worth approximately 100 trillion yen. The Japanese market is said to account for just over approximately 8% of this figure. This makes Japan the second-largest market in scale following the US (approx. 38%)1). While all major pharmaceutical companies have long hoped to also simultaneously include Japan in their global development plans if possible, there were some barriers to entry into the Japanese market for drug development. These included the guidelines of regulatory agencies and relationships with domestic pharmaceutical companies. From approximately 10 years ago, the globalization of domestic pharmaceutical companies and changes to national policy meant that these regulations were eased, resulting the gradual lowering of such barriers. However, cultural and linguistic differences remain as invisible barriers. Some data have indicated that Japan ranks 24th in terms of countries in which global clinical trials are being conducted2). More global clinical trials should be conducted in Japan as it ranks second in the world in terms of market scale. One particularly large issue that exists as a barrier currently is the unification of global operations. This issue has its roots in linguistic differences. While many problematic aspects of information sharing and methods of communication between global and local teams have been solved by means of increased utilization of IT, observing “time constraints”, which are crucial in global clinical trials, remains very difficult, because of some facts including that decision-making process takes a long time due to communication gaps.
　In this context, certain sample size should be gathered within the limited time in order for Japan to boost its presence in global development. In the same manner that the number of opportunities for PROs in the US to engage in activities to solve issues faced by pharmaceutical companies increased (increased costs associated with prolonged trial periods and opportunities missed due to delayed market launches), the increased number of global clinical trials being conducted in Japan meant that more requests were made to PROs for subject recruitment work as a means of directly solving the issue of strict time restrictions for case enrollment.

Image of subjects recruited from advertisement in Japan
　Subject recruitment involves a series of activities. We have described this flow as a “leaking pipe” (Figure 1). In Japan, subject recruitment often refers to activities for recruiting subjects from within hospitals or from outside hospitals (advertising etc.). There is little understanding in Japan that subject recruitment is a process. This is because in Japan, in-hospital activities including subject recruitment (in-hospital poster and leaflet production, informed consent supporting material creation, dropout reduction countermeasures (retention)) are almost always conducted by the clinical research coordinator (CRC) within hospitals on a daily basis. Surprisingly, activities are conducted at a level that would be allocated a budget overseas, basically for free. As a result, these activities are not considered to be of particular importance in Japan. Of course, performing in-hospital GCP or duties in accordance with determined protocol are not special activities. However, as stated above, the content of recent clinical trials is also becoming increasingly difficult. Informed consent forms (ICFs), which are translated from English for the increasing number of global clinical trials, include Japanese phrases that are difficult to understand and consist of thick documents, making it difficult to obtain the understanding of patients (particularly elderly patients). In addition, many clinical trials do not offer many benefits for the subjects.
　Japanese clinical trials provide an extremely high level of service by means of detailed response offered by CRCs belonging to the site management organization (SMO). This situation is highly unique worldwide and, while it has various advantages, it is considered to be one reason for the higher costs of clinical trials in Japan than in other countries. However, in recent years, it is becoming difficult to promote subject enrollment and retention even with high quality Japanese CRCs. With regards to enrollment in particular, CRC in-hospital recruitment activities are limited if the clinical trial is targeting subjects who are not originally present within the hospital. Moreover, because problems are also likely to arise when coming into contact with patients for the first time after they have been referred by advertising, many CRCs and medical institutions do not highly regard patients referred by advertising. This needs to be taken into consideration when formulating subject recruitment strategies. As this is an important aspect, a more detailed explanation is offered below.

Figure 1. “Image of a leaking pipe”

　For example, let us imagine that some sort of clinical trial advertisement is implemented to recruit subjects. This may involve advertising within Japan alone, or advertising with a global central campaign. In either case, the advertising expressions and recruitment flow must be approved by the institutional review board (IRB) of the facility at which the clinical trial is being conducted. What needs to be considered is that approval of advertisement implementation may not be approved for clinical trials at major hospitals (teaching hospitals etc.) in Japan. There is a strong perception in Japan that patients recruited within the hospital and those recruited by advertisement are completely different patient demographics, and that the latter are likely to cause problems. One reason for this is the fact that higher compensation is provided than in other countries worldwide. Compensations of 7,000 to 10,000 yen are paid on average for each visit to hospital. This is not a particularly high amount considering medical costs, the costs of commodities and transportation in Japan. However, as medications and basic medical care are free during the clinical trial period, these compensations are a significant financial benefit to patients. Patients who enroll in the trial in order to receive these compensation are often thought to be focused on money and have difficult personalities.
As major hospitals (teaching hospitals etc.) in Japan are extremely busy, they are extremely crowded due to long waiting times even though they only handle treatments of serious diseases and emergency patients. The hospital can resemble a war zone and it can be considered extremely troublesome if advertising for clinical trials results in the hospital being directly contacted, thereby impeding daily medical care activities. There is also a risk that visits by large numbers of patients to the hospital as a result of advertising could take away time from medical care for general patients. As patients recruited through advertising do not necessarily have any medical record-based information or data on their history of disease, there are many cases considered ineligible before consent can be acquired, which is not the case for the hospital’s own patients. Generally, about two out of three patients cannot actually be assigned to a trial. This is another reason for the negative attitude of many major hospitals regarding accepting patients recruited by advertisement.
While this may sound like a joke, situations that place a heavy burden on patients such as the following case may also occur. A certain medical institution allocates just one slot per week on a weekday morning for clinical trial treatment (no convenience or options for patients). Patients who are referred to the said trial pay several thousand yen out of their own pocket as “medical expenses not covered by health insurance (selective medical expenses)5) and, in some cases, are also required to pay over 10,000 yen for tests performed at the initial examination. Depending on the results of these tests, they may not be able to participate in the trial, resulting in them not even being able to receive reimbursements for these costs. Most other medical institutions participating in the same trial offer few time slots and days of the week for the treatment, allowing for hospital visits to be adjusted easily. Moreover, medical expenses not covered by health insurance and test costs do not need to be paid. Thus, when considering in comparison with the tough conditions set by the aforementioned medical institution, you only have to consider whether you would select the former medical institution when participating in a clinical trial to see why it is so difficult to recruit patients for clinical trials. In addition, requests may be made from such medical institutions that “all referred patients should be confirmed as 100% eligible for the trial before referral”. This is an extreme but true case example of a medical institution that should not be targeted for patient referrals by advertisement.
　To prevent any misunderstandings, it must be stated that both patients of the hospital and patients referred via advertising are suffering from the same disease. There is no difference in data for application following clinical trial participation based on the fact that most trial drugs tested in patients referred via advertising are available on worldwide markets. Based on our experience, the results of differential analysis of various protocols have also indicated that there is no difference between hospital’s own patients and patients referred via advertising. One difference between hospital’s own patients and patients referred via advertising is a tendency for higher motivation for clinical trial participation amongst patients recruited via advertising than hospital’s own patients. Thus, responding to placebo responders needs to be taken into consideration for trials for which the primary outcome measure is a subjective symptom. Conversely, as patients recruited via advertising tend to exhibit good adherence in terms of taking the medication, they are said to have lower non-compliance and dropout rates. In addition, many clinics and major hospitals including teaching hospitals in Japan do accept clinical trial advertisement. The question whether a facility accepts advertisement may also depends on the disease type or protocol. Based on the fact that clinical trial advertisement conducted by CROèe Inc. alone has resulted in the assignment of 7,000 to 8,000 cases to PII/III trials6) indicating that not all medical institutions hold negative views of clinical trial advertisement. However, one must take into account the fact that when the selected facility is a regional core hospital or teaching hospital, the said hospital may not have the capacity to sufficiently accept patients referred via advertising and the fact that clinical trial advertisement may not be approved in the first place.

Key stance on subject recruitment strategies in Japan
We will now discuss points in formulating subject recruitment strategies based on the specific situation in Japan as described above. We will start with the answer to what the most important thing in subject recruitment is. That is facility selection. It is not an overstatement to say that successful facility selection determines the success or failure of the clinical trial in 80% of cases. After taking general facility selection requirements (e.g. whether there is a sufficient number of patients that can be targeted within the hospital, whether equipment is sufficient, whether the responsible physicians have enough experience etc.) into account, there are two broad requirements for facilities from the viewpoint of subject recruitment. The first is being a facility that patients referred via advertising will find it easy to select. An example of this will be shown below. The second requirement is facility staff (CRC/medical staff/PI) having a positive view of patients referred via advertising. Even if excellent advertising gains the sympathy of many patients and such patients who want to participate in the trial are referred to the said medical facility, all efforts will end in vain if the facility has a negative view of patients referred via advertising and such patients are not treated well. When described in terms of the leaky pipe shown above, successful facility selection means selecting a pipe with good water flow that is unlikely to become leaky.

　SMO provision of facility information (facility feasibility investigation) is one aspect of the facility selection process that is unique to Japan. SMOs have concluded supporting contracts with facilities mainly comprising clinics. University hospitals and national hospitals etc. also each have clinical trial centers and corporate consultation counters, and these gather facility information within many groups. If the sponsor wishes to obtain facility information in order to conduct a clinical trial, a questionnaire is presented to the survey reception counter at each SMO and the university or national hospital, and a request for a survey is made. On average, it takes approximately 2 weeks to 1 month for results of the questionnaire responses to be received from each party. At SMOs supporting many facilities, responses are received from dozens or at least several facilities. The sponsor then performs evaluation based on these survey results, successively visits the facilities, gathers detailed information and then concludes contracts. Surprisingly, SMOs or hospitals do not get paid for any of the activities related to such facility surveys. Survey costs can only be recovered if the SMO or hospital is able to conclude a clinical trial contract based on the results of the survey. This has both advantages and disadvantages. As the sponsor is not responsible for paying for anything until conclusion of the survey, they can freely make a survey request. Disadvantages include the fact that survey-related tasks can be waste unless the facility is selected as the clinical trial facility, therefore, facilities try as hard as possible to be selected. Thus, data is likely to be biased, making the objectivity of data questionable.
　If a non-leaky pipe is successfully selected, one now needs to consider how to ensure water flow through the pipe, which is a method of subject recruitment. Because the effects of subject recruitment differ depending on the disease based on whether subjects are recruited from inside or outside the hospital (Figure 3), the method of subject recruitment needs to be carefully considered. Clinical trial advertising is not universal and there are generally many latent patients. Patient groups attending a medical institution are considered to be effective subject groups. Subject recruitment within the hospital can cover a wider range of diseases and pathologies. Moreover, as long as the facility is a medical institution, it is possible to recruit latent patients.
　Facility selection is an element of subject recruitment strategy formulation that affects subject recruitment. It involves taking into consideration convenience for referred subjects (large number of candidate facilities, large number of possible days and time slots for hospital visits, proximity from station etc.). To make sure that candidate patients are gathered through subject recruitment and ensure that gathered patients are responded to without being lost by facilities, facility convenience needs to be fully taken into consideration at the facility selection stage.

■Notes and Disclaimer
• This document was prepared to provide information to CROèe Inc. stakeholders.
• While we made every effort to offer the latest and most accurate information while preparing this document, this does not guarantee its completeness, accuracy and validity.
• CROèe Inc. takes no responsibility for any damage of any kind that may occur as a result of using this document.
• CROèe Inc. holds copyright for these materials and the authors of cited materials hold copyright for those cited materials.
• The company names, products and service names etc. described in this document are registered trademarks and trademarks of the respective companies.
• The copying, reproduction, diversion or redistribution of this document without permission in whole or in part is strictly prohibited.
• This article is edited version of actual written article of Daisuke Maki, Corporate Officer and Director of Public Relations and Educational Promotion Office, CROèe. INC.

【For inquiries regarding this】
CROee, Inc
URL：www.croeeglobal.com/
TEL： 03-5953-2108 FAX：03-5952-1887 Mail：imran@croee.com