After huge changes in the regulatory system, Japan has become the largest market for clinical trials in the Asia-Pacific region for both local and global studies and is now a country of choice in clinical development maps.
Previously regulatory lag was a huge hurdle for global drug developers. One good example of such lags is Doxil which got global approval in 1999, wherein the drug got approval in Japan in 2009. There are many such examples, but now things have changed fastly. It would take approx four years for drug approval in Japan while, 1.5 years for approval in the USA.
A significant change in recent years was a greater acceptance of overseas data and clarity around the regulatory framework in Japan. In addition to the new guidelines released by Japan’s regulatory body for medicines, efforts were made by the regulatory body to reduce the study startup timelines. These changes reduced the timelines drastically for drug approval to 1.5 years in Japan.
Now Japan has become one top countries to choose for drug development for the following reasons.
Top reasons to choose Japan for your clinical development plan
- After the US and China markets, Japan is the world’s third-largest single pharmaceutical market and second-largest for prescription drugs,
- With a rapidly aging population (26.6% over 65 years old in 2016) increasing the demand for healthcare and medicines,
- A mature local market and renewed economy,
- Nationally-funded healthcare infrastructure with universal health insurance,
- A large and adherent patient population,
- A strong emphasis on quality and precision in clinical research,
- Incentives such as priority or conditional-approval programs for new medicines for rare diseases (high unmet needs) such as orphan diseases,
- Acceptance of foreign study data and reliance on bridging studies,
- Improved clinical trial start-up timelines,
- NDA Drug approval timelines have been reduced significantly (as little as one year), and
- The modified approval process with an increased number of reviewers for faster approvals.
To conduct clinical trials and obtain drug approval, the typical process in Japan compared with other countries and requires strategies to plan drug development. Having a properly designed development road map would help to minimize hurdles, delays and save both cost and time.
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Drug development in Japan
To achieve a successful drug development in Japan, one need to follow a step wise process as below
- Step 1 > Understand the Japan regulatory
- Step 2 > Develop a roadmap
- Step 3 > Appoint a In-country caretaker
Step 1: Understand the regulation that applies to your product
The legislation in Japan that governs pharmaceuticals and medical devices administration is the PMD Act and regulates clinical research, manufacturing, marketing, labeling, and safety of drugs, diagnostics, regenerative medicines, and medical devices.
The sponsor can submit the clinical trial plan to the MHLW for the following medicinal substances, instruments, and processed cells
- Medicinal substances with active ingredients that differ from those of drugs listed in the Japanese Pharmacopoeia and those of drugs already approved for marketing
- Medicinal substances that have the same active ingredients as those of drugs listed in the Japanese Pharmacopoeia and those of drugs already approved for marketing and differ from them in terms of routes of administration
- Medicinal substances that have the same active ingredients as those of drugs listed in the Japanese Pharmacopoeia and those of drugs already approved for marketing but differ from them in terms of percentage of active ingredients in the drug composition, indications and effects, and dosage and administration
- Medicinal substances with the same active ingredients as those of drugs that have already been approved for marketing as drugs that differ inactive ingredients from drugs listed in the Japanese Pharmacopoeia and drugs already approved for marketing, and for which the reexamination period specified under the PAL has not passed from the date of marketing approval
- Medicinal substances that are expected to be biological products
- Medicinal substances that are manufactured by using genetic modification technology
- Instruments whose structure, usage, efficacy, effect, and performance are different from those already approved
- Instruments that are medical devices approved as those that are clearly different in structure, usage, efficacy, effect, and performance from medical devices approved and that have the same characteristics in structure, usage, efficacy, effect, and performance as those whose post-marketing usage result survey period has not passed
- Instruments that are expected to be biological products
- Instruments manufactured by using genetic modification technology
- Processed cells that are expected to be regenerative medicine products
The Sakigake pathway for breakthrough and regenerative medicines includes substantial regulatory and scientific support for development plans, rolling NDA submissions, and an accelerated review period.
In certain conditions, the Japanese regulatory does not require large studies, rather may just ask for small studies with few patient populations to confirm the safety and efficacy.
The Sakigake pathway scheme accelerates the development of new drugs, especially innovative therapies that have been priority or fast track review designation similar to the US Food and Drug Administration’s Breakthrough Therapy (BT) designation and fast track approach.
Along with the Sakigake pathway, Japan has added another unique scheme, “Conditional Early Approval,” which allows highly advanced therapies for incurable diseases to be brought to the Japanese market without Phase 3 trial results.
Any party can utilize the “Conditional early approval” scheme in Japan. The full submission should be made within 10 years or less (this period is set by the authority) with the clinical data equivalent to a Phase III trial.
This scheme provides some benefits, both on the financial and development sides; clinical data could be collected in Japan and the product sold in Japan with a limited clinical trial, while it is still being developed in the US, EU, and/or other countries.
Understanding the regulatory would help to identify the right category and pathway for drug development and having an consultation with the PMDA would be a great idea before planning. Please note that the consultation with the PMDA is a paid service.
Step 2: Develop a roadmap
In order to have successful launch of a drug, you need to have a predefined scientific roadmap to avoid glitches and time delays. Once you are clear with the regulatory that applies for the category of your drug, then the things for planning would be better and more clear.
One of the strategy in drug development is global drug development.
Global Drug Development Strategy
Developing drugs in more than one region would have more benefits compared with confining the drug development in Japan. Here are the following advantages of global drug development.
- Prevention of unnecessary duplication of clinical trials
- Efficient and cost-effective drug development
- Solving the drug lag issue with global simultaneous drug development
- Data submission benefits for drug approval
So for a global drug development strategy, you need to find answers to the following
- What are the basic requirements to conduct a global clinical trial?
- What are the basic points to consider in designing a global clinical trial?
- What are acceptable sample size and proportion of Japanese/ Asian subjects?
- Management of concomitant medications or therapies in a GCT
- In which phase of the study can the drug development plan move into Japan?
Before planning a global trial its advisable to have a PMDA consultation to
- To get advice from PMDA officially
- Take advice and suggestions from the regulatory experts
- To make a “binding” agreement with PMDA prior to GCT
One big strategy to overcome lags is submitting the IND in a global country like the USA and parallelly conducting Phase IIa studies and Phase III studies in both the USA and Japan.
Clinical studies and study designs
When you consider Japan in your development route map, then you need to keenly review the study designs. Here also the PMDA consultation plays a crucial role before planning any study design.
Global studies including Japanese sites in the protocol incorporate bridging studies from Asian countries such as Korea and/or Taiwan.is one consideration while developing a strategy.
Impact of “ethnic factors” on the acceptability of foreign data
- Minimize duplication of clinical data
- Bridging requirements for extrapolation of FCD to a new region
- Enhance global development
Strategies to overcome these challenges
- Complete clinical data package
- Adequate Characterization of
- Efficacy and Safety
- Clinical Disorders evaluated using medical & diagnostic definitions acceptable in the region
- Determine the requirement of the bridging Study
- Ethnic considerations
- PK, PD > safety, tolerance, efficacy or dose-response
- Extrinsic (food, climate) culturally or behaviorally determined
- Intrinsic factors (genetics) greater impact on the ability to extrapolate
Management of Development Strategies based on PK-profile
Adaptive design is regarded as an efficient method for clinical trials in order to increase the success rate of a new drug in development and recently has been actively discussed and implemented by many researchers.
The dose-response curve differs based on the ethnic groups like in Japanese and other regions. Most of the drugs marketed in Japan, the USA, and other countries differ in the approved doses, and the Japanese dose is usually small. Therefore MHLW / PMDA requires clinical data obtained in the Japanese population in application dossiers unless there is ground for exemption.
Cost shall be considered while designing a clinical trial as clinical trial running costs are higher in Japan and are due to
- Slow patient recruitment
- Complex payment systems
- Higer site costs and staffing
To reduce cost, you need to consider the following measures that may help
- Designing clinical trials that require less patient recruitment (Moderns clinical study designs).
- Planning the best payment systems
- Sponsors need to negotiate with the site staff for salaries
Strategies for patient recruitment
Some of the strategy for better patient recruitment includes
- Setting up an online portal and social media and referring them to the clinical trial site.
- Collaboration with patient recruitment organizations.
- Partnering with doctors, pharmacies, companies that process prescriptions, organizations providing regular medical check-ups, and nursing care specialists.
- Medical and prescription claims database.
Step 3: Appoint an In-country caretaker
To conduct a clinical trial in Japan, it is recommended to have a CRO with a strong local presence to conduct clinical trials. In Japan, the term CRO is not popular and rather is regarded as an In-country caretaker. An in-country caretaker is a person who handles all the clinical trial-related aspects right from registering, importing, and collections of study.
A sponsor can initiate, operate, monitor, and manage a clinical trial, including preparation of standard operating procedures, complete studies on the quality; and prepare a clinical trial protocol, etc. However, in some conditions where the sponsor is not a local person may entrust the operations concerning a clinical trial to a CRO within the appropriate scope. However, the final responsibilities concerning the quality and completeness of clinical trial data remain with the sponsor.
Moreover, if in the case where the sponsor is not a local person needs to appoint an in-country clinical caretaker. An In-country caretaker is one who resides in Japan (including the representative of a foreign legal person holding office in Japan) so that he carries out the necessary procedures for sponsoring a clinical trial and ensure that necessary measures are taken to prevent the occurrence or spread of hazards to public health and hygiene.
A sponsor may delegate part of his or her duties and functions related to sponsoring and managing a clinical trial (or post-marketing usage result survey of a product) to a CRO. A CRO may perform any or all of the following services:
- Help to plan development strategy
- Conduct of Phase I to Phase III trials
- Preparation of approval application form, approval application summary, and attachment documentation as well as application
- Post-marketing usage result survey
- Carrying out the responsibilities of the in-country clinical caretaker and designated marketing approval holder (D-MAH)
- Trial-related services other than those mentioned above
- Consultation regarding development and approval/license
- Consultation regarding statistical analysis
- Quality assurance/audit and consultation regarding quality assurance/audit
- Training services
If the CRO acts as an in-country clinical caretaker, then shall take the necessary measures to indemnify/compensate trial subjects in the same manner as the sponsor. The sponsor must enter into an agreement with the CRO, which covers the following:
- Scope of the functions and obligations
- Procedures for the conduct of the delegated tasks
- The provision that the sponsor may ascertain if delegated tasks are carried out properly and smoothly in accordance with the above procedures
- Matters concerning instructions to the CRO
- A provision that the sponsor may ascertain if its instructions are observed and that the delegated tasks are carried out properly and smoothly in accordance with the instructions
- Matters relating to reporting by the CRO to the sponsor
- Matters relating to indemnification to trial subjects
- Other necessary matters concerning the delegated tasks.
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