Clinical Studies In Japan Today: Another Look At The World’s Second-Largest Prescription Drug Market In A Post-Pandemic World
The pharma industry has compelling reasons to include Japan in clinical trials and the country’s responses to the COVID-19 pandemic have only furthered the country’s appeal to the rest of the pharma industry. Japan’s large patient population, mature local market and flexible data regulations for clinical trials are just a few reasons to involve Japan in global studies. To become more attractive to global sponsors, Japan has undergone sweeping changes to create a climate conducive to clinical development programs by aligning drug approval timelines with those of the US and Europe.
As with most countries, Japan’s industry had to adapt to the current environment, thus creating a system open to decentralized clinical trials (DCTs). As incredibly important as Japan is, there were and still are multiple challenges pharmaceutical companies tackle while looking to expand their global reach into Japan. Sponsors are faced with challenges such as patient recruitment, site management, and changing local regulations.
One of Japan’s regulations is that overseas sponsors must use in-country clinical caretakers (ICCCs) to sponsor trials on overseas companies’ behalf if they do not have an entity located in Japan. At a fundamental level, ICCCs manage both safety reporting and regulatory interactions such as registering the trial. ICCCs may also be contract research organizations (CROs), which plan and supervise the clinical trial’s development from planning to execution. In addition to the CROs, Site management organizations (SMOs) are extremely important in Japan as they bridge the gaps between the sponsor pharmaceutical company, CROs and Japanese medical institutions. They provide total administrative and practical support to medical institutions and patients during clinical trials.
Because of the additional support SMOs provide, many large Japanese pharmaceutical companies also use them for clinical trials in addition to CROs. SMO support can be the key to conducting successful, high-quality clinical trials. SMOs provide support to trials via clinical research coordinators (CRCs) and Site management associates (SMAs). CRCs improve the quality of clinical trials in by managing key areas such as patient eligibility, informed consent support, hospital visits, testing schedules and other clinical trial materials such as preparing case report forms (CRFs). To facilitate smooth clinical trials, they provide additional support to clinical research associates and assist medical institutions with audits/regulatory inspections.
SMAs routinely perform administrative tasks such as invoices, documentation, supporting IRB submission and reviews, preparing sites for clinical trials, and supporting both audit and regulatory inspections. SMO support is so vital that larger CROs, such as the CMIC Group, have developed and added in-house SMOs into their offerings.
Reducing Regulatory Issues
Efforts have been made to improve regulatory challenges in Japan during the past decade, which have resulted in an environment that is significantly friendlier to clinical trials. This is not to say that starting a clinical trial in Japan is without challenges.
Since the Ministry of Health, Labor and Welfare (MHLW) regulates clinical trials in Japan, sponsors must adhere to MHLW’s standards all the way from sponsoring to clinical trial execution and drug approval. Overseas and local sponsors find that they must adhere to the Good Clinical Practices (GCP) set forth by the Pharmaceuticals and Medical Devices Agency (PMDA) as well as local regulations, such as the Pharmaceutical and Medical Device Act and Clinical Trials Act.
While CROs monitor clinical trials to make sure they run smoothly and adhere to all laws and regulations, SMOs are imperative to streamline the process in the medical institutions. SMOs collaborate with CROs as they manage the regulatory framework to verify that the trials adhere to all laws and regulations. As CROs verify compliance, and the sponsor to investigators and institutional review board (IRB) committees, SMOs coordinate with them throughout the process to provide practical and administrative support which streamlines processes and validates that the clinical trials are adhering to all regulations.
Simplifying Patient and Site Management
One of the major challenges in Japan, similar to other regions, relates to patient recruitment and engagement. Japanese patients are part of the country’s national health insurance system. This can be problematic because patients may not be motived to participate in clinical studies. Additionally, common practices and methods utilized heavily in other regions to improve patient engagement, such as telemedicine and home nursing, are not yet widely used in Japan. This is a result of the country having relatively more medical institutions than any other country, which also may be close to home for many patients than any other country.iii Thus, telemedicine has not been necessary before COVID-19 and is still going through a time of adjustment.
SMOs use their extensive knowledge to guide clinical trial sponsors to high-potential candidate sites. Business Development Dept., Director at CMIC Group’s SMO Business, Mr. Masanobu Minamino, explained to Citeline that SMOs essentially manage medical institution sites for each clinical trial. Before a trial is even scheduled to take place, an SMO conducts feasibility studies to verify that it will be successful in the medical institution setting.
Recognizing the challenges of continuous patient engagement, especially while facing current environmental factors, SMOs provide each study with clinical research coordinators (CRCs) to serve as the liaisons between doctors and patients. Patients and CRCs communicate daily regarding medical questions or adverse events, and this continuous engagement and care means patients are less likely to drop out of a study. This type of patient and doctor interaction is crucial for the success of clinical trials, especially DCT trials, where patient engagement needs to be carefully cultivated and monitored.
Since both global and local pharmaceutical companies use SMOs, they are accustomed to supporting both types of clients. While there are few differences between supporting both clients, there are a few important differences. CMIC Group SMO Business, Managing Executive Officer, Mr. Kohei Sakazaki, discussed the main differences between global and local clients for SMOs. “Japanese guidelines might be different from the global guidelines. So based upon global clients’ requirements, we just look for the medical institution that can respond to our requirements. The same applies to differences between larger and smaller clinical sites. The primary variance is generally workloads between the sites, which includes administrative tasks such as institutional review board submission. Larger sites take more steps and more time to complete, making SMOs critical for CROs and sponsors.”
Customizing Japanese Decentralized Clinical Trials
Prior to the pandemic, many corporations were exploring DCTs but had not started implementation. While patients traditionally went to medical institutions due to the easy accessibility previously mentioned, patients avoided hospitals during the first pandemic wave. As a response to the pandemic, some new clinical trial methods were introduced with guidance from regulatory agencies.
The MHLW issued the Timely/Exceptional Handling of Consultations Using Telephones and Other Telecommunication Equipment Due to the Spread of Novel Coronavirus Infections guidance on April 10, 2020, which became permanent in October 2020. As a result, new clinical trial methods that do not depend on live patient visits to medical institutions, such as trials using DCTs or virtual clinical trials (VCTs), are now becoming more available in Japan.
Neither medical institutions nor patients were accustomed to DCTs, meaning adoption was slow. However, these models have become increasingly necessary as Japan, along with the rest of the world, experiences additional pandemic waves. Since the cost effectiveness of DCTs is still being assessed, sponsors/CROs must adapt current DCT/VCT models to Japan with support from SMOs, to minimize costs and increase both patient and medical institution comfort. As these models are adopted, companies with both CRO and SMO functions become even more important due to language and regulatory barriers for sponsors.
CMIC Group’s CRO Business, Future Design Department Director, Mr. Shuji Ozawa, recently addressed how they customize DCT/VCT models to address language and regulation obstacles. CMIC Group’s clinical trial platform is like many DCT models, but since the challenges and situations are different for each DCT/VCT, they customize it for Japan by “analyzing the regulation gaps, consulting with PMDA, analyzing the vendor settings and creating procedures” to ensure that the trial is free from any potential hurdles. CMIC also highlights the need for CROs/SMOs to collaborate with digital partners to ensure that trials proceed flawlessly, from system or device introduction to productivity. This includes assisting with the system introduction to site staff, patients, and investigators. Their current CRO and SMO structure works seamlessly to provide trial management and healthcare services to patients using digital technologies.
As Japan continues to be included in global clinical trials, there is a strong need to increase DCT capabilities going forward. One potential challenge facing Japan right now is the investment in technologies used for DCTs/VCTs in other countries. Ms. Mari Kawamura, CMIC Group’s SMO Business, Team Leader of Business Planning, notes that “venture companies are not so prevalent in Japan compared with the United States because of the regulations as well as our business, environment and culture. However, having said that, if you look at recent years and the venture companies engaging in DCTs, the number is increasing.” SMOs have field knowledge at the local level, which includes medical institutions, and communities. As DCTs/VCTs continue to become more widely accepted, SMOs are essential for successful implementation in all aspects.
Looking At a Hybrid Future
Although its regulatory bodies are actively producing guidelines to make clinical trials easier in Japan, the process is still full of complications that can delay such studies. Japan’s response to COVID-19 has been patient-centric, allowing for patients to participate in both virtual and decentralized trials. It is clear that these trials, in addition to live sites, are essential to the future.
An experienced SMO with knowledge of the regulatory issues, documentation, local culture and connections with the local medical institutions s essential for the success of clinical trials. As Japan moves towards adopting DCTs/VCTs, it is wise to select a partner with both CRO and SMO capabilities so that they are able to seamlessly implement digital technology. While the CRO aspect of the company creates the study and protocol designs to incorporate digital solutions, hence working with digital partners, the SMO will coordinate with medical institutions, patients and investigators to assist them with the use of the technology. As we move forward to a digital word, a SMO/CRO partner is essential to the growth and success of clinical trials.
- CMIC CEO/COO leadership interview article
- Roundtable Discussion Report: The Benefits of Clinical Trials in Asia Are Significant if Done Right.
- Whitepaper: Gateways to Asia Market Access in Japan and South Korea