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Document-based Inspection to CTD M3(Quality studies)/M4(Non-clinical studies other than GLP studies) data

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Overview

Importance of the Reliability of Application data

  • Based on the application data submitted, risk-benefit balance of efficacy and safety is evaluated, and then the validity of indications/performance, dosage and administration, and precautions is reviewed.
risk-benefit balance of efficacy and safety
  • If the data submitted on approval application is unreliable, efficacy and safety in humans cannot be evaluated.
If the data submitted on approval application is unreliable, efficacy and safety in humans cannot be evaluated.

Laws & Regulations for Securing the Reliability of Application Data

＜Pharmaceuticals and Medical Devices (PMD) Act(Note)  Article 14, Paragraph 3＞　
The person who intends to obtain the approval referred to in Paragraph 1 above shall make an application by attaching data/documents related to the results of clinical studies and other data/documents to the application form pursuant to the provisions of the Ordinance of the Ministry of Health, Labour and Welfare（MHLW ordinance). In this case, if the drug for the application is a drug specified by the MHLW Ordinance, the data/documents must be collected and prepared in accordance with the standards specified by the MHLW Ordinance.
(Note)Act: Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices, Act No.145 of August 10,1960

What are “other data/documents” in the PMD Act Article 14 Para 3?

＜Article 40 of the Enforcement Ordinance of the PMD Act＞
The data/documents to be attached to the application form set forth in Article 38, Paragraph 1 or Article 46, Paragraph 1 pursuant to the provisions of Article 14, Paragraph 3 (…) of the Act (…) shall be the data/documents set forth in the relevant items.

1 Data/documents for approval of drugs: a. Data/documents on origin or history of discovery and usage conditions in foreign countries, etc. b. Data/documents on manufacturing process, specification, study methods, etc. c. Data/documents on stability d. Data/documents on pharmacological action e. Data/documents on ADME f. Data/documents on acute toxicity, subacute toxicity, chronic toxicity, genotoxicity, teratogenicity and other tox g. Data/documents on study results such as clinical studies.Common Technical Document (CTD) format is commonly used for application data.

What are “the Standards specified by the MHLW Ordinance” in the PMD Act Article 14 Para 3?

＜Article 43 of the Enforcement Ordinance of the PMD Act＞

The data/documents as stipulated in the latter part of Article 14, Paragraph 3 of the Act (…) must be collected and prepared according to the following in addition to those specified in the Ministerial Ordinance on Good Laboratory Practice for Nonclinical Safety Studies of Drugs (MHW Ordinance No. 21, 1997), the Ministerial Ordinance on Good Clinical Practice for Drugs (MHW Ordinance No. 28, 1997), and the Ministerial Ordinance on Good Post-marketing Study Practice for Drugs (MHLW Ordinance No. 171, 2004)..1) The data/documents concerned shall be those accurately prepared based on the results obtained in studies conducted for the purpose of preparing them. 2) If any study results that raised a question about the quality, efficacy, or safety related to the drug for the application are obtained in the study in the preceding item, the study results shall be reviewed and evaluated, and the results shall be described in the data/documents. 3) The raw data that became the basis of the data/documents concerned shall be retained until the date of disposition to the effect that approval of Article 14, Paragraph 1 or Paragraph 15 of the PMD Act is given or not given. However, this does not apply if the storage of data/documents is extremely difficult..

Series for Notification of inspection procedure

Two notifications describe in detail in terms of "document-based or on-site inspection" specified in Article 14, Para 6 of the PMD Act..Document describing the handling of remote inspection, as one of the inspection methods (English translation available)..Supplemental document detailing remote inspection.
 

​What’s the document-based inspection?

The following should be confirmed by inspecting raw data/documents for quality studies, non-clinical studies, and clinical studies in the application data.
  • Studies in the NDA dossier for new drugs have been appropriately conducted in an ethical and scientific manner in accordance with GLP/GCP and the study plan/protocol.
  • Data/documents of the studies in the NDA dossier have been prepared appropriately and accurately in accordance with the standards provided in the Article 43 of the Enforcement Ordinance of the PMD Act, or so-called “Reliability Standards of Application Data” .
CTD Modules 3 to 5 are subject to document-based inspection (Article 40, Para 1, Item 1-(b)-(g) of the Enforcement Ordinance of PMD Act).
Scope of Inspection following the Reliability Standards of Application Data
Reliability Standards of Application Data (Subject to document-based inspections)
  • Unique to Japan
  • Created for the purpose of recurrence prevention of drug-induced harm that have occurred in Japan in the past
  • ​Common minimum requirements necessary to ensure the reliability of all data/documents (especially non-GxP studies)  in application data

ALCOA+ vs Reliability Standards of Application Data

International principles for ensuring reliability
Attributable: Identification of the person performing the work
Legible: Maintaining data readability and traceability
Contemporaneous: Recording data simultaneously with the work
Original: Maintaining original format
Accurate: Creating scientifically accurate data

Complete: Ensuring all data without missing data
Consistent: Maintaining consistency throughout the data lifecycle
Enduring: Ensuring maintenance of data for the future
Available: Data can be accessed as needed

Requirements in the Reliability Standards of Application Data for application data are in common with internationally recognized principles!!

Two ways to conduct the inspection to CTD M3(Quality studies)/M4(Non-clinical studies other than GLP studies)

  • There are 2 ways to conduct a document-based inspection to  CTD M3(Quality studies)/M4(Non-clinical studies other than GLP studies).
  • PMDA decides the way in a critical consideration for the risk/importance of application data (e.g., application category).
1.Normal way、Overview：Raw data reconciliation Verification of supporting records Review of preparation process of NDA dossier、Raw data submission and Study plan/Final report submission：Necessary、Format：Document review、Days needed：11 business days　2.Simplified way、Overview：Review of preparation process of NDA dossier、Raw data submission and Study plan/Final report submission：Not necessary、Format：Web interview、Days needed：1 day

Document-based inspection（Normal way）

  • Data/study(s) targeted for the inspection will be selected based on the risk/importance of data.
  • The applicant will be required to submit the study plan and final report , raw data/documents of the data/study(s) selected.
  • The inspection is conducted at desktop (self document review) in almost all cases.
  • The main focus of the inspection is to reconciliate the raw data/original record with results in the CTD M3(Quality studies)/M4(Non-clinical studies other than GLP studies).
  • In addition, supporting records and QC/QA process of CTDM3(Quality studies)/M4(Non-clinical studies other than GLP studies) will be reviewed in the inspection.

Timelines

NDA：E-mail will be sent to PMDA with the applicant name, product name, application date and contact person's information. NDA supplementary documents will be submitted.、Scheduling：PMDA will notify the applicant of inspection dates and target data/study(s) up to 2 months before the last day of inspection by E-mail、Document submission(1)：The study plan and final report specified by PMDA will be submitted within 3 weeks from the notification.、Selection of data/study(s)：PMDA will select the raw data/documents to be inspected (e.g., specific lot/time point(s) for quality studies) and request to submit on 20 business days before the last day of inspection.、Document submission(2)：The raw data/documents requested by PMDA will be submitted up to 10 business days before the last day of inspection.、Inspection：1) The raw data/documents will be reviewed, 2) questions/issues will be compiled and 3) which will be then sent to the applicant. Only if the questions/issues cannot be resolved, a web interview will be conducted.PMDA will notify the web interview by 2 business days in advance if conducted.

Data/documents to be submitted

NDA：Refer to the official notification(e.g. CTD, Detailed Index of Documents, GLP Test Facility Information Sheet etc)、Upon application、Gateway System、Document submission(1)：Study plan・Final report、Within 3 weeks from the request、Gateway System、 Document submission(2)：Raw data/documents、10 business days before the inspection date、Gateway System・On-line Storage systems、 Inspection：Response to questions/issues、PMDA specifies(2 business days)、E-mail (MS Excel file)

Types of raw data/documents to be submitted

  • A typical inspection will require the submission of raw data and other relevant records which are directly linked to the test results in the CTD.
  • There are two types of data/documents for Normal way: "Data/documents to be submitted as default" and "Data/documents to be submitted as needed." (However, there may be cases where the volume of data/documents is reduced by the conditions and scope specified) For "Data/documents to be submitted as needed", inspectors will request to submit during the inspection period (or before) only if they determine to be necessary.
Quality studies 1.Data/documents to be submitted as default：Raw data (any records directly linked to study results (such as numerical values) in the application data)、For stability studies、temperature/humidity records、Deviation records(If applicable)、Any documents describing QC/QA(If applicable) process employed、“Description of raw data/documents”2.Data/documents to be submitted as needed：Records on receipt and management of samples、Records on receipt, management and quality of reference standards、Records on maintenance of apparatus/equipment、Other data/documents necessary for inspection、Nonclinical studies 1.Data/documents to be submitted as default：Raw data (any records directly linked to study results (such as numerical values) in the application data)、Deviation record(If applicable)、Any documents describing QC/QA(If applicable) process employed、“Description of raw data/documents”

Important Notice for raw data/document submission

  • Please coordinate with the inspector individually if the raw data/documents to be submitted are in a file format that cannot be read without specific software (instead, may ask presenting with a screenshot or sharing the screen at a web interview).
  • Please make the orientation of the documents consistent, as there have been cases where the orientation of submitted PDF files has not been consistent when storing submitted data/documents in a cloud or other system.
  • The “Description of raw data/documents” should include (1) Document showing the folder structure, (2) explanation of the flow of data, and (3) other information useful for efficient inspection (see the next item).
  • Please submit the “Description of raw data/documents”  in the same method as raw data/documents (i.e., the cloud system or  the Gateway System)
  • Raw data/documents to be submitted will be selected as follows. It may be further narrowed in consideration of data volume.

Quality studies: Lot number, measurement time point, etc. (could be selected by measurement items)
Non-clinical studies: All raw data/documents, but could be selected by measurement items, treatment groups, etc. 

Description of raw data/documents

Please submit ”Description of raw data/documents’’ including  the following imformation (1)-(3), otherwise it might lead to an increase in the number of questions or an extension of the inspection period.
(1)Document showing the folder structure (explains in detail the structure of raw data/documents submitted)
  • Submit a document showing the folder structure with raw data/documents and should also send it by e-mail.
  • Organize the data/documents per data/document type listed in the previous table.
  • Name the data/documents so that the inspectors make it possible to guess the contents.
  • Create subfolders for each category of documents.
In the final tier, include not only the file name but also the corresponding page range.
 (2) Explanation of data flow
Create a certified copy of the raw data/documents and use it to address the following items
  • The flow of data (Lot number, measurement results, Chromatogram, Calculated results, etc.) in red boxes or highlight them. 
  • Comments if necessary.
Create a certified copy of the raw data/documents and use it to address the following items：The flow of data (Lot number, measurement results, Chromatogram, Calculated results, etc.) in red boxes or highlight them. 、Comments if necessary.
(3) Other information useful for efficient inspection
e.g.) If the raw data/documents were recorded in a language other than Japanese and English
  • Although do NOT have to translate all of the contents, translate (in Japanese or English) enough for inspectors to be able to follow the flow of data (study items, measurement results, etc.) at least.
  • Translation of specific parts of raw data/documents may be requested during the inspection period.  

How to submit raw data/documents

(1)On-line Storage systems such as Cloud systems
  • The applicant shall provide the inspectors permission to (read-only) access to the system.
  • The following systems are not able to be used under the PMDA’s network environment.

  e.g.) Systems requiring application installation
  　　 Systems requiring change of security settings
            Systems requiring file download

  • There are some requirements for word search, word copying, etc.
  • A connection test will be performed prior to uploading the raw data/documents.  
 (2) Electronic Study Data Submission System (“Gateway System”)

URL：https://esg.pmda.go.jp/Ssk/comn001p01.init [Japanese only]


For details, please refer to the following official notification!
Procedure for Remote Inspection as a Part of Compliance Inspection on Drugs and Regenerative Medical Products[197KB]

Document-based inspection（Simplified way）

  • The main focus of the inspection is to confirm the preparation process for the NDA dossier by Web interview.
  • Therefore, an applicant is NOT required to submit the study plan, final report and raw data/documents.

Timelines

NDA：E-mail will be sent to PMDA with the applicant name, product name, application date and contact person's information. NDA supplementary documents will be submitted.、Scheduling：PMDA will notify the applicant of the day of web interview up to 1 months before by E-mail.、Web interview：The preparation process for the NDA dossier will be explained during the interview.

Items to be explained during Web interview

（1）Background information of NDA

（2）Preparation process for NDA dossier 
  • QC/QA and approval process (including person/entity responsible) from the raw data to CTD (NDA dossier) will be clearly identified using a flow chart.
  • The records of approval for each step will be presented.
1.SOP etc 2.QC・QA record, Approval record 3.SOP etc 4.Record 5.SOP etc 6.QC・QA record, Approval record 7.SOP etc 8.Record 9.SOP etc 10.QC・QA record, Approval record
 
（3）Applicant’s procedure for confirmation
  • Applicant’s procedure to confirm the completion of the preparation process by any other party will be explained if the above-mentioned step2 was not performed by the applicant.

Reference materials

Self-inspection checklist Q&A for non-clinical studies

The checklist was revised to restore its original purpose as a reference for applicants' self-inspections and is available on the JPMA website.

Regulations and Notifications

Drugs
Regenerative Medical Products

Related Information