Academic Report on Japan Clinical Trial Strategy for a Class III Medical Device

1.0 Executive Summary

Japan leading medical company, Japan Med (JMED) acquired CardioGenesis’s Axcis (1st Generation) Percutaneous Myocardial Laser (PML) system and has now developed Axcis Plus (2nd Generation), the first in the world (Hypothetical product).  

Japan Ministry of Health, Labour and Welfare (MHLW) recently approved the Axcis Plus for Orphan device registration pathway for the following reasons:

The targeted population size of Japanese patients are less than 50,000 in Japan There is still no alternative treatment and methods available for patients with medically refractory angina caused

by diffuse coronary disease The Axcis Plus shown potential for expanded importance for the targeted indication based on the Research &

Development results  

Axcis Plus is a state of the art robot-assisted medical device that doesn't utilize conventional laser light for treatment. The newly invented laser light, known as “Omega” uses Non-Ionizing Radiation Electrom Beam as the energy source, not laser properties. Together with the robot technology, Axcis Plus offer much more safety, precision, and control during Percutaneous Myocardial Omega (PMO) Therapy.

JMED is confident this novel therapeutic treatment is better at delivering oxygenated blood to the myocardium, thereby improving patients with refractory or end-stage angina not amenable to percutaneous coronary intervention. According to the Japan Medical Device Nomenclature (JMDN), Pharmaceuticals and Medical Devices Agency (PMDA) classified Axcis Plus as a Class III device.

2.0 Objective of Phase 3 Clinical Trial

Even after excellent animal test, phase 1 trials on safety assessment, early and late phase 2 trials on assessment of safety efficacy of Axcis Plus. The Orphan Device Expedited Review still required a phase 3 trial. Emergo Group (2016) reinforced the notion and reported that it is pivotal to complete the phase 3 trials in order for JMED to obtain marketing authorization registration.

Japan MDC (2014) reported the phase 3 trials have to be conducted in a larger group of patients in controlled and uncontrolled trials. As a result, JMED is now preparing to perform phase 3 trials clinical trial in Japan to evaluate the Axcis Plus’s clinical safety and efficacy of Japanese population under Japanese medical practice and environment.  

2.1 Phase 3 Clinical Trial Objective

The phase 3 clinical trial core objective is to address the further safety and effectiveness in a larger group of patients. It is also an opportunity to answer the research questions (problem statement) on whether Axcis Plus whose new design structure and direction for use is more superior in term of safety, efficacy and performance compared to the 1st generation.  Equally  important question is to find out whether patients find it acceptable in term of the pain level.

JMED hopes to achieve measurable benefits such as reduction in symptoms and pain during intervention, improved exercise tolerance and enhanced quality of life for the patients.  

3.0 Selection of Medical Institution, Principal Investigator, and Sub Investigators According to Emergo Group (2005) Ordinance of the Ministry of Health, Labour and Welfare (MHLW) No. 36 on Good Clinical Practice for Medical Devices. JMED will  have to select a medical institution that meets the specific qualifications specified in Article 54 and Principal Investigator and Sub Investigators who have to meets the qualifications specified in Article 62.

The Selection of Medical Institution, Principal Investigator, and Sub Investigators will not be issues as there are plenty of good standards medical institutions for JMED to select to run the trial.

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This is made possible because of the Network for Multi-Center Clinical Trials (NMCCT) initiatives in year 2003 by Japanese Medical Association (JMA) and Japanese MHLW that have trained the respective medical institution, investigators, and staffs in producing high-quality clinical data and standardized testing procedure as reported by Chiu (2013).   

3.1 Rational for Clinical Trial Design There are several type of design of clinical trial with different layers of complexity. The selection of the trial design must be per-tained to Axcis Plus research questions of “does it reduce pain or discomfort?”, “Is it be as good as or better than 1st generation?” and “Does it have fewer adverse reactions?”.

Chiacchierini (1994) reported the use of randomized controlled trials can maximize the clinical relevance of the data and minimizing confounding factors. Matthews (2006) also championed using of randomized controlled trials to assess new treatment and its intended use.

The following are the strength and weakness of Randomized Controlled Trial that JMED, Medical Institution, and Investigator have considered:  

3.2 Strength and Weakness of Randomized Controlled Trial Design The strength of Randomized Controlled Trial Design for Axcis Plus are:

Rigorous evaluation (Effect of Percutaneous Myocardial Laser versus Omega Therapy and effect of treatment versus placebo group)

Evaluation of single variables (precisely defined patient group – patients with severe angina symptoms that had exhausted all forms of conventional therapy aged 40 to 60 years)

Prospective design (Clinical data are collected on events which happen after execution on the actual study) Hypothetic deductive reasoning (seeks to falsify, rather than confirm the hypothesis factors) Potentially eradicates bias by comparing two otherwise identical groups Meta-analysis (ability to combine the numerical results of several similar trials at a later date)

The weaknesses of Randomized Controlled Trial Design for Axcis Plus are: Required big budget in term of monetary and time-consuming (big scale would need more resources too) Surrogate end points are often used in preference to clinical outcome measure (diverse measure of endpoints) No success case to learn and improve or failure case to re-learn and improve (many Randomized Controlled Trial

Design are either never done) Difficult to blind, randomize, control and may constitute hidden bias (imperfect randomization, failure to

randomize all eligible patients and to successfully blind assessors too)   Overly dependent on physician technique (Device modifications may occur during trial)  

As phase 3 trial is the main frontier assessment of safety, efficacy and performance of Axcis Plus (new use and new methods), JMED have decided to seek the “gold standard” in trial design and employ Randomized Controlled Trial (RCT) which Pencina and Peterson (2016) confirm it is very good in generating new finding.

The trial group will be subjects to concurrent controls, which will allows trial subjects to be randomized between control and treatment groups. This is utmost important because it can help reduce selection bias such as patient bias (the placebo effect) and investigator bias and to control any deviation factors.   

As JMED’s Axcis Plus is running a company-sponsor clinical trial, It is a must to comply with Japanese Pharmaceutical Affairs Law (PAL). There are various guidances and guidelines from the Ministry of Health, Labour and Welfare (MHLW). However for scientific and regulatory consultation, the official source of assistance is to seek consultancy services from Pharmaceuticals and Medical Devices Agency (PMDA) (no date) on the following:

Pre-consultation on  clinical trials and regulatory submissions (and how to improve the trial) During-clinical trial assessment on whether a proposed study complies with the requirements for regulatory

submission (such as patient safety, ethics, sample size and endpoints) Post-clinical trial action on data collection and analysis techniques Product Marketing Authorization methods

3.3 Protocol for the trial - Reason for choice of sample size

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Greenhalgh (2006) reported that the sample size for trial participants should be large enough to have a high chance of detecting worthwhile difference and also detecting no good or benefit exists if it is not found during and after the trial. In order to adhere to the International Conference on Harmonisation (ICH) Good Clinical Practice and Japan Good Clinical Practice (JGCP).  JMED and its Principal Investigator will be referencing on the historical control data (literature review) from the previous Axcis (1st Generation) studies as the basis for Axcis Plus trial design.

The objective is to use the previously observed report to plan an adequate sample size that are able to detect a real difference between treatments and at the same time ensuring patient safety. PMDA consultancy will be required at this stage so as to determine whether there are any issues and problems to compare historical control group made up of western trial subject to Japanese-only (Japanese population) ethnic group.

The chosen statistic for calculation will be based on uncorrected chi-square for analysis. Using a two-sided statistical level of significance of 0.05 with a statistical power of 80% as the acceptable rate.  

40 patients in each group were calculated as the effect size necessary to detect differences. The total trial enrollment was established at 84 patients to account for any dropouts. This sample size is being approved by PMDA as it is deemed feasible and desirable as it provides the opportunity for a statistically and clinically meaningful result.   

3.4 Primary and Secondary endpointsThe following are the proposed primary and secondary endpoints and their statistical measure of data for analyzing between the intervention and control groups. The endpoints are to provide statistical evidence of interaction between the overall treatment effect between treatment and placebo group during and after Axcis Plus Interventions. The proposed primary and secondary follow-up period of the study to be 6 to 30 months after the intervention. All analyses have to be performed at PMDA approved clinical research institute.

3.5 Endpoints to Evaluates Effectiveness

Time to event measurement on how long it takes to observe the outcome of interest in a set time period including: Difference in Canadian Cardiovascular Society angina classification score (baseline to 6 and 30 months) Difference in health status from the Seattle Anginal Questionnaire (baseline 6 to 30 months)

3.6 Endpoints to Evaluate Safety

Binary measurement on whether or not an event has occurred consisting: Primary Endpoints in the Death and cerebrovascular accident, acute coronary syndrome and any emergency

hospitalization Secondary endpoints including major adverse cardiac events at 30 days The composite of cardiac death, acute Q-wave and non-Q wave myocardial infarction (MI), revascularization

procedures for procedure-related complications or coronary ischemia and stroke at 6 and 30 months Using Kaplan-Meier event rates from 6 to 30 months to compare within each score quartile by randomized

treatment group

3.7 Endpoints to Comparing Secondary Assessment

Ordinal scales of measured outcomes including:   Primary endpoints in the changes of ejection fraction, medication usage, exercise time and quality of life from

baseline examination to 6 months   The difference in health status and anginal symptoms using a semi-quantitative instrument employing the Medical

Outcome Study General Health Survey The difference in global and regional radionuclide perfusion scores at rest, peak stress, and redistribution using

semi-quantitative and quantitative methods from baseline (6 months to 30 months) The difference in all exercise test parameters including duration, time to angina, and time to ST-segment changes

from baseline (6 and 30 months)

4.0 Japan Good Clinical Practice Regulation

The Japanese Good Clinical Practice JGCP is essentially a modified version of the rule developed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.

The Japanese medical device JGCP describes the principal investigator's' qualifications and responsibilities. The description includes the investigator's' responsibility for all aspects of the clinical trial at the investigational site, such as patient selection criteria, patient care, monitoring, and reporting.  It also includes guidance on the clinical trial protocol and data analysis, data

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handling, and recordkeeping; a description of Data Safety Monitoring Boards (DSMB); and requirements for educating and training end-users.

The JGCP requires each clinical trial protocol to be reviewed by an Institutional Review Board (IRB). IRB can be established by medical institutions, academic organization or other legally authorized organization. Alternatively, heads of other institutions can jointly organize them.

The JGCP describes the specific requirements of an IRB, including its responsibilities, composition, function, and operation.

Each IRB is required to have at least five members. At least one of the five members' primary area of interest must be in a nonscientific area. One member must be independent of the institutional site, and one member must not have any relationship with the clinical trial.

JMED’s Axcis Plus clinical trial design and strategy will have to seek approval from the IRB and the various ethical board stipulated in JGCP prior to commencing.

The ethical principles embodied in the Declaration of Helsinki form the basis for the informed-consent document. The general principle covered the rights, safety and wellbeing of clinical investigation patients.  

4.1 Clinical Trial Notification

In the capacity of company-sponsor, JMED, and its Principal Investigator have to submit the developed clinical trial protocol for review and follow the regulatory steps to gain approval for the clinical trial. Firstly, JMED has to submit a clinical trial notification (CTN) to PMDA.

PMDA review standpoint on approving clinical trial are:  

Rationale for development of the device Intended use in clinical practice Non-clinical test for Performance and Safety (Appropriate evaluation based on its concept) Clinical evaluation for Clinical trials and literature investigation (Appropriate evaluation based on its place in the clinical practice Uses Essential Principles

RAPS (2015) reported that PMDA offers pre-consultation to review the clinical trial protocol, followed by a final official consultation meeting in which JMED will receive minutes of the meeting itemizing down the outcome, changes required and the final steps to submit the clinical trial study application.

After the final review and approval by PMDA, JMED can proceed without any written notice from PMDA.

4.2 Japan Clinical Trial Audit

Kiyohito & Martin (2005) reported the Japanese Pharmaceutical Affairs Law (PAL) dictate the clinical trial regulation from the development of clinical trials and how to conducting them. PMDA is the regulatory body overseeing and auditing the dossier review and approval process on clinical site and clinical report data check.

PMDA will conduct clinical site check on the clinical investigational sites to audit the processes and accuracy of documents. The document audit consists of reviewing report, preclinical data, clinical trial protocol and the analysis plan. The checking is on the accuracy, completeness and compliance to Japan Good Clinical Practise (JGCP).

Good Document Practices have also to be adhered for patient confidentiality protection provisions such as informed consent form and ethical submission to the Institutional Ethics Review Committees following the recommendation in the Declaration of Helsinki.

JMED will have to work with Japan Primary Registries Network (JPRN) to comply the Helsinki Declaration guidelines that every clinical trial must be registered in a publicly accessible database before recruitment of the first subject. The three registries are:

The University Hospital Medical Information Network (UMIN CTR) Japan Pharmaceutical Information Center - Clinical Trials Information (JapicCTI) Japan Medical Association - Center for Clinical Trials (JMACCT CTR)

5.0 Challenges From Designing and Conducting The Trial

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The biggest challenge for Axcis Plus trial will be during the intervention because of the innovation nature and design, it may depend heavily on physician technique that could cause device modifications and device specific failure during trial. At such, training is utmost importance for the physician and Principal Investigator to minimize any deviation.  

The lack of experienced physician and Principal Investigator will also limit the options of conducting multi-site clinical trials which is an important issue as Japan is relatively large and the long commute time for the trial participants would deter from following through the whole-cycle of the trial.

Before, during and after trial, data collection such as patients self-report are critically important so as to validate and verify the result. Abdel (2010) reported the methods to address these challenges is to use the Interactive Voice Response System (IVRS) and/or Interactive Web Response System (IWRS) that would be able to protect the identity of the patient by assigning them a specific number. This is to endure data provided and the results reported are accurate and credible, and under no circumstances, the integrity, rights, and confidentiality of trial subjects were safeguarded

Another challenge is on how to manage the patient in the placebo group. Expert point of view pointed out the superiority of using a placebo control. Chow & Liu (2014) reported that placebo treatment in a control group can study the measurable benefit of the intervention.  

For the case of Axcis Plus trial, the patients studied had severe angina symptoms and had exhausted all forms of conventional therapy. As a result, there is no ethical concerns of withholding treatment when effective treatment are available and thus, fully comply with the Independent Ethics Committee (IEC) and Helsinki Declaration guidelines that when known treatments exist, they should be use in place of a placebo.

The other various challenges for Axcis Plus trial during the different phases are discussed below:

Development of the clinical standard operating procedures (SOPs) may not be in compliance with many Japan regulatory guidelines

Type II error in studied endpoint- If a power analysis is calculated and is lower than the 80% power level, this trial runs the risks of a Type II error (which will not be able to detect the significance value between the 2 groups)

Informed consent not addressing the factors that may influence an individual’s decision such as education level and culture

Ethical patient recruiting practices, it is important to review advertisements to ensure appropriate effort are being used to engage and recruit trial subject in participating

Economic considerations in monetary compensation to the trial subject Insurance protection of the device by applying medical indemnity for collateral damages allowable Comparison of trial population to target population, is it a fair representative of the final target population Materials such as questionnaires, interview scripts, instructions that will be provided to participants during the

study. How the research staff will protect participants welfare and how participant information and data will be stored

and protected to prevent unauthorized access The translator does not have the bilingual competency.

Interpretation of probabilistic estimate can be challenging, understanding the strengths, weakness, and validity of the methods are critical. Therefore, constant upgrading, upscaling and uplearn new skills are important in modern day of evidence-based intervention.

The conflict of interest disclosures, declaration of funder and sponsor and the specific role of the physician, Principal Investigator and others personnel will have to be submitted to PMDA truthfully and ethically so as to endure no implication after the trail especially during the submission to respectable journal database to be recognised as a peer-reviewed medical journal paper.

As the first controlled trial in Japan, a single trial may not be sufficient to assess long-term efficacy and safety, as a result, there must be further prospective evaluation to assess potential effects on patient care as well as validation in other cohorts which will add on the financial responsibilities. Therefore, budget planning is important for JMED to have the monetary power to plan for more and longer trial to further address future challenges such as new technique, devices improvement/modification and any post-clinical trial adverse events that required post-mortem investigation.

6.0 Reporting Requirements - Adverse Events Reporting

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Azuma, K. & Iseki, H. (2013) reported mandatory safety reporting requirements during clinical trial were introduced in Japan’s regulations in 2005. Even though, International Standards such as ISO 14155:2011 (Clinical investigation of medical devices for human subjects— Good Clinical Practice) and GHTF/SG5/N5:2012 (Reportable Events During Pre-Market Clinical Investigations) are used by Japanese regulations to serve as a basis facilitating regulatory convergence in safety reporting. There are differences in the requirements for reportable events and reporting time frame as compared to Pharmaceutical Affairs Law (PAL) and the Ministerial Ordinance on Good Clinical Practice for Medical Devices.

Comparison between the treatment-related

reportable events and reporting time frame

guidelines as the table on the right:

6.1 Reporting Requirements – Completion of Trial  

For international standard, ICH (2005) documented in the Guideline for Good Clinical Practice, E6(R1), Clause 4.13 that upon completion of the trial, the investigator should inform the institution, the investigator should provide the IRB with a final summary of the trial’s outcome and any final reporting to the respective regulatory authority with their requirement.

In Japan context, under the Ordinance of the Ministry of Health, Labour and Welfare (MHLW) No. 36, Article 69, Paragraph 3, on Good Clinical Practice for Medical Devices. Upon completion of the trial, the investigator shall report the completion in writing and submit a written summary of the trial’s outcome to the head of the medical institution. After which, the head of the medical institution shall need to notify the IRB and the JMED of the fact and a summary of the trial’s outcome.

The final reporting has to be aligned and complied with the following Japan regulatory requirement:

The Pharmaceuticals Affairs Law (PAL) (Law No.145, 1960), Revised July 2002), PAL Enforcement Ordinance (Cabinet Order No.11, 1961), Revised December 2003, and PAL Enforcement Regulations (Ordinance of the Ministry of Health and Welfare No.1, 1961, Revised July 2004)

Ordinance of the Ministry of Health, Labour and Welfare No. 36, 23 March 2005 (JGCP) Japanese Ministry of Health and Welfare, Yakushokukihatsu No.0720005, 20 July 2005 Operation of Good

Clinical Practice for Medical Devices (JGCP Manual) Office memo of the Office of Medical Device Evaluation, Evaluation and Licensing Division, Pharmaceutical and

Food Safety Bureau, MHLW, Essential Documents for Criteria Concerning Clinical Tests for Medical Devices, 20 July 2005

With the finalized clinical data, Axcis Plus can now attach this final report to the STED documents for the submission of marketing authorization registration through the “Shonin” (New technology) approval route as reported by RAPS (2015).   

7.0 Conclusion

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The author has based on the case study known as the Blinded Evaluation of Laser Intervention Electively For Angina Pectoris (BELIEF) trial reported by Nordrehaug and Fauls (1999) to compile up this report.

This prepared report and the recommendations were not intended to be exhaustive regarding all of the contributors to a clinical trial in Japan. Clinical trials involve intensive planning, extremely expensive, and require extensive reviews, approvals and control. The key to success is to choose the right standard, guidance and regulatory guideline to follow.

However, in the course of researching, the author cannot find many updated official MHLW and PMDA regulatory guidance documents in English. At such, the author hopes in the future the “Harmonization-By-Doing” Japan-US program as reported by HBD WG4 (2013) can help to champion more updated regulatory guidance documents in English for the various non-Japanese stakeholders.      

End of Report

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