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South East Asia 

2nd March 2022

The Research Quality Association South East Asia (RQA-SEA) Regional Forum, in collaboration with Japan Society of Quality Assurance (JSQA), successfully organized a virtual regional forum on 18 November 2021. The forum was attended by approximately 70 quality professionals across the Asia-Pacific (APAC) region via Microsoft Teams Meeting. The forum started with the welcome speech from Dr. Jun Li, APAC Head of Regulatory Compliance at Johnson & Johnson (J&J), and the Chairman of the RQA SEA Regional Forum, and Dr. Teiki Iwaoka, Chairman of JSQA International Affairs Committee, and was followed by three presentations on PMDA GCP Remote Inspection, Decentralized Clinical Trials (DCTs) and updates of the Japanese Regulations and a panel discussion about Vendor Managements by guest speakers and panellists.

The first presentation on PMDA GCP Remote Inspection was delivered by Mr Naoki Tsutsumi from the National Center of Neurology and Psychiatry. There had been changes to the method of GCP inspections globally as onsite inspections were limited due travel and local restrictions amid the COVID-19 pandemic. PMDA had responded to the pandemic by establishing and developing the following measures to continue its inspection activities.

1) Establishment of remote inspection environment under COVID-19 outbreak

  • Issue of “Handling of Implementation Procedures for Immediate Document-based Inspection and GCP On-site Inspections due to COVID-19 outbreak”.
  • Clarify the definition of remote inspection and notify the possibility of applying the method to PMDA inspections
  • Initiate pilot trial of Applicant Inspection with remote method
  • Questionnaire survey for the applicants

2) Development of an environment in which remote inspections can be applied in peacetime regardless of COVID-19 outbreak

  • Notification of procedure for Compliance Inspection was issued on 31 Aug 2020
  • Procedure for Remote Inspection as part of compliance inspection on drugs and regenerative medical products was issued on 16 Nov 2020

PMDA remote inspection would be conducted by examining the records or documents, which form the basis of the inspected trials and studies, from the PMDA office remotely through the cloud system and video conferencing system. PMDA would communicate with applicant about how remote inspection would be conducted and address any questions from applicant. Applicant would be required to provide the required documentation 10 business days before the main inspection. During the pre-inspection (within 10 business days of main inspection), inspectors would review the documentations presented and query the applicant if any concerns were detected, as appropriate. The main inspection would be conducted via video conferencing and concerns identified during the pre-inspection would be discussed. After the inspection, applicant would be required to resolve concerns according to the outcome of the inspection as soon as possible.

When preparing the documents for remote inspections, the applicant should consider proper procedure when converting paper records to electronic records to ensure completeness and adequate contrast of the scanned records. Documentations may be shared via cloud applications (access should be provided to inspectors) or via mail delivery. If documents would be shared via CD/DVD, these should be mailed to PMDA by 10 business days prior to the main inspection. If paper documents would be submitted, applicant should discuss with the inspector for an agreed timeline for submission.

As of March 2021, PMDA had conducted remote inspection for around 177 products and 75 applicants.

The next presentation on Decentralized Clinical Trials (DCTs) was delivered by Mr. Ren Libao from J&J. DCTs are defined as those executed through telemedicine and mobile/local healthcare providers (HCPs), using procedures that very from the traditional clinical trial model. All activities in DCTs are ideally remote or digitalized methods, for example, online patient identification, online recruitment, virtual pre-screening, eConsent, home healthcare visits, eClinical outcome assessments, direct to participants medical shipments, community labs, remote monitoring and wearable, results sharing, etc. There were different models of DCTs, such as, virtual model (all assessments done virtually), hybrid model (some assessments can be done virtually or at the site), combo model ( some sites within the trial adopt the virtual or hybrid DCTs model, while other sites use the conventional model).

The DCT program at Janssen, Trials2You, was an initiative that provides the ability to conduct elements of a clinical trials outside of the traditional clinical trial site, with usage of home healthcare, digital health platforms and solutions, direct-to-participant medical product, local lab closer to home, etc. Some benefits for participants may include greater flexibility and convenience, increased access to clinical trials and reduced burden to caregivers. Participating trials sites may also see reduced burden, greater flexibility and more time for patients. The industry may potentially benefit from faster recruitment, improve retention, increased diversity and obtain data more representable of the real world.

There were some challenges of DCT implementation to consider from regulatory perspective and from study operation and quality and compliance perspective.

1) From regulatory perspective:

  • Applicability and performability of law, regulation, guidance or procedures for DCT
  • Acceptability of DCT study data and implementation approach from Data review and inspection perspective (e.g., home nursing certificate or qualification, digital tools’ qualification)

2) From study operation and quality and compliance perspective:

  • Availability and quality of technology and services (e.g., telemedicine system or tools, home healthcare providers, etc.)
  • Oversight of home nurse and local healthcare professionals and quality control. (e.g., GCP violation, protocol adherence, data integrity, etc.)
  • Data privacy protection when digital tools are used in clinical trials. (e.g., eConsent, telemedicine, etc.)

Lastly, some potential issued identified during the audits conducted for DCTs were shared:

1) Documentation for risk assessment to justify approach for systems validation

2) Management of user accounts

3) Process for audit schedule, conduct and documentation

 

The third presentation on update on the Japanese Regulations was shared by the JSQA International Affairs Committee members, including Dr. Teiki Iwaoka, member of JSQA, Mr. Takahiro Hanai from Daiichi Sankyo and Dr. Shuhei Hagiwara from Nissan Chemical.

The Pharmaceuticals and Medicinal Devices Law (PMDL) implemented in 2014 was revised from the Pharmaceutical Affairs Law (PAL) to include medical devices. The main points of revision were:

1) Enforcement of safety measures for pharmaceuticals and medical devices.

2) New regulations considering medical device characteristics.

3) New regulations considering regenerative medicine characteristics.

 

There were further revisions to the PMDL made in 2019, which included:

1) Provision of pharmaceuticals safely and promptly:

  •  “Sakigake” application nomination program
  •  Conditional / term-limited authorization
  •  Electronic labelling of package insert
  •  Product barcode for pharmaceuticals packaging

2) Availability of pharmaceuticals in any place in Japan

3) Compliance enforcement for pharmaceuticals marketing

 

There were revisions to the ministerial ordinance under PMDL for Good Laboratory Practice (GLP), Good Clinical Practice (GCP), Good Vigilance Practice (GVP), Good Post-marketing Study Practice (GPSP), Good Quality Practice (GQP) and Good Manufacturing practice (GMP). Some of the key revision points were discussed during the forum and summary of the revisions can be found below.

From 1 Apr 2020, on agrochemicals, the following tests must be performed under GLP studies:

1) Agrochemical Formulations (Category: Physical and Chemical properties)

2) Honeybees and wild bees (Category: Ecotoxicity)

3) Birds (Category: Ecotoxicity)

4) Estimation of exposure of pesticide users in the field (Category: Toxicity)

 

Key revisions to J-GCP Guidance amendment dated 31 Aug 2020:

1) Re-defined “Study Drug” including Investigational Drug, Comparator Drug, Concomitant Drug, Rescue Drug, etc. which are specified by protocol (J-GCP Article 2)

2) Removed requirements of PI and Sub-I’s job title in the protocol (J-GCP Article 7.1, 15.4.1)

3) Added requirements for management of “re-defined Study Drug” (J-GCP Article 16, 26.2, 39)

4) Added requirements for handling safety information or reporting of “change the definition of Study Drug” (J-GCP Article 20, 26.6, 48)

5) Revised requirements for qualifications of IRB establisher (J-GCP Article 27.2)

6) Clarified handling process of CRF when Interim CSR is created for NDA submission (J-GCP Article 47)

7) Added processes when clinical trial is continued as post-marketing clinical study (J-GCP Article 56)

 

There were some GMP non-compliances and PMDL violations noted in Japan over the past few years. In order to ensure good manufacturing practice in Japan, the regulators had implemented some measures in a few areas:

1) PMDL revision in 2019:

  • Corporate governance and Compliance system
  • Responsible Board Member appointment for Regulatory affairs

2) GMP ordinance was revised in 2021:

  • Adherence to the approved procedure
  • Introduction of ICH-Q10: Pharmaceutical Quality System (PQS)
  • Securement of data integrity

3) GMP on-site inspections without any notice.

4) Whistle-blowing collection system and disclosure of on-site inspection

 

The panel discussion on Vendor Management was led by Mr. Xavier Tey, member of the RQA-SEA Regional Forum committee and joined by panel speakers, Ms. Liuqiong Wu from GlaxoSmithKline (GSK), Mr. Roy Toh from Janssen and Ms. Stacey Basham from AbbVie. Mr. Xavier Tey had presented comments on behalf of Ms. Stacey Basham as she was unable to join the forum due to unforeseen circumstances.

In recent years, more companies were taking a risk-based approach on the qualification and management of vendors. In risk-based vendor management, analytical dashboards were used to identify signals and trends, such as trending vendors risks, trending across compounds or therapeutic areas, etc. The focus on metrics were also shifted from performance metrics to quality metrics. When contracting vendor services, companies may perform background checks, risk assessment on GxP risk, information and security risk, etc. and any mitigation plan to control risks may be included in the contract with vendors.

The COVID-19 pandemic had accelerated the adoption of technology. To minimize disruption to trial activities caused by the COVID-19 restrictions, there were more vendors providing virtual or digital services, such as home healthcare services, direct-to-participant services, community laboratory etc. More companies or regulators had adopted the remote audit or remote inspection methods in view of the restrictions. The pandemic had also driven the uptake of risk-based vendor management to mitigate risk. As the industry evolves, there is a need to balance the adoption of technology with the requirements from the quality perspective. Local regulatory requirements and data privacy requirements should also be taken into consideration as companies shift toward digitalizing during the pandemic. While audits would still be performed periodically, there could be more real-time oversight on quality via metrics.

As the industry is still at an early stage of adopting new technology, there were challenges and lack of real solutions at this point as the companies, vendors and regulators continue to evolve and adapt. Active communication between various stakeholders continues to be the key to identify and mitigate risks and to ensure the conduct of a successful clinical trial.

At the end of the forum, Dr. Li and Dr. Iwaoka expressed their appreciation to the speakers and attendees for their active participation and the insightful discussion during the forum. The team looks forward to the possibility of hosting a face-to-face forum next year and hope the forum continues to serve as a platform for quality professionals in APAC and East Asia to share and exchange information.

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