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FAQs on Electronic Study Data Submission (Excerpt)

Provisional Translation (as of February 2017)
 

This document summarizes inquiries on electronic study data submission received by the PMDA in a Q&A format.
Please utilize these Q&As to resolve problems and questions related to electronic study data submission.

Notice:This is an English version of the following FAQs on electronic study data submission published on February 3, 2017: some questions from “1. Questions on new drug review and consultation”; a question from “3. Questions on electronic submission gateway”; “4. Questions on CDISC-conformant electronic study data”; and “5. Questions on electronic study data on clinical pharmacology.”


1. Questions on new drug review and consultation

Q1-6:In the technical conformance guide 3.6.1, it states, “Before transferring the electronic study data, the applicant should perform a validation, and necessary explanation should be given for any violations identified”. Is it permissible to provide the necessary explanation for violations at the Pre-NDA consultation?

Q1-6-1:If a sponsor cannot complete datasets or perform validation prior to the Pre-NDA consultation, what should they do?

Q1-16:When a sponsor performs validation with software that the vender claims is compatible with the software used by the PMDA, and then corrects data or explains the results, are there any particular points to consider?

Q1-17:If a detected violation is attributed to a bug of the validation software, is it necessary to correct the data?

3. Questions on electronic submission gateway

Q3-6:Will the PMDA perform validation of CDISC-conformant data when the applicant submits the electronic study data in response to inquiries?

4. Questions on CDISC-conformant electronic study data

Q4-1:What is the base date for the “Date Support Begins (YYYY-MM-DD)” and the “Date Support Ends (YYYY-MM-DD)” in the PMDA Data Standards Catalog?

Q4-2:In the case where electronic study data is added or replaced during review, is it necessary to follow the standards with the same version number as those at the time of original submission?
If the “Date Support Ends” of the version used at the time of the original submission has already passed, what procedures should be followed?

Q4-3:Which files or contents will be included in the scope of CDISC-conformant validation performed by the PMDA?

Q4-4:When is it necessary to submit electronic datasets of integrated analyses (ISS/ISE)? What is the scope of electronic data on ISS/ISE that must be submitted?

Q4-5:When is it necessary to submit electronic study data as attached documents in response to inquiries during a review? What is the scope of the electronic data that is subject to submission on such occasions?

Q4-6:If the protocol, etc., is prepared in Japanese, is it necessary to translate the information on the design of the clinical study into English, and store it in the SDTM Trial Design Model domain? Please indicate parameters and codes that the PMDA requests at a minimum for the TS domain of SDTM.

Q4-7:In Section 3.(1)c of “Notification on Practical Operations of Electronic Study Data Submissions,” it states, “Use the WHO Drug Dictionaries Drug Code (WHO DDs) when coding drugs.” Please explain the background of the need to use WHO DDs, and give an example of how to store WHO DDs data under the CM domain of SDTM.

Q4-8:In Section 3.(1)c of “Notification on Practical Operations of Electronic Study Data Submissions,” it states, “If data were collected in units that are commonly used where conversion of the data to those in SI units is possible, separately store the converted data in SI units in the SDTM dataset as data in the standard units and submit them.” Please indicate the scope of variables that need to be converted to SI units. Also, if data are collected in units other than SI units, how can the original data and the converted data be stored within the SDTM dataset?

Q4-9:Some values need to be displayed in Japanese on analysis results, and such values need to be stored in datasets in Japanese. In such cases, should only datasets with alphanumeric values be separately prepared for electronic study data submission?

Q4-10:If datasets include languages other than English or Japanese, what procedures should be followed?

Q4-11:When translation is performed (e.g., from Japanese to English), is it necessary to certify the correctness of the translation?

Q4-12:When Japanese datasets will be submitted in addition to alphanumeric datasets, is it necessary to create a dataset definition document for each dataset?

Q4-13:If analysis software is used that requires no explicit program creation, is it permissible to submit an operational log instead of a program? Or will “the submission of specifications that show the analysis algorithm” be separately requested? Please indicate examples of the contents to be described in the “specifications that show the analysis algorithm.”

Q4-14:If datasets in a format other than the CDISC standards are converted into a CDISC-conformant format for submission, and if the source datasets and the Annotated CRF are to be submitted together as an explanation of traceability, under which folder should they be stored?

Q4-15:When submitting electronic data of an integrated analysis (ISS/ISE), in which folder should they be stored?

Q4-16:When submission of the analysis program is difficult, submission of the “specifications that show the analysis algorithm” may be considered. In which folder should they be stored?

Q4-17:In order to explain the process by which the variables of ADaM datasets were created, reference data used to create ADaM datasets (reference tables such as Lookup tables, Metadata, etc.) are to be submitted; in which folder should they be stored?

Q4-18:Data used to impute missing data (e.g., multiple imputation) are to be submitted as an ADaM data source; in which folder should they be stored?

Q4-19:In Section 4.1.1.4 of the “Technical Conformance Guide on Electronic Study Data Submissions,” it states, “the character sets and the encoding system used to create the dataset should be described in the data guide;” please give specific examples of the character sets and encoding system that must be described.

Q4-19-1:In connection with Q4-19 above, how can information be obtained on the encoding system used?

Q4-19-2:As shown in one of the examples in Q4-19 above, when the encoding system is UTF-8, is it necessary to include further information such as USC-2 for the character set, UNICODE?

Q4-20:If the application is to be made based on the results of an interim analysis, is it permissible to include data obtained after the cutoff of the interim analysis up to the time of application with data submitted for the application?

Q4-21:Is there anything special to consider when the SDTM IG v3.1.2 Amendment is used for the creation of the SDTM datasets?

Q4-22:Is it possible to store and submit the datasets/files not conforming to CDISC in the folder that is defined to store SDTM datasets or ADaM datasets?

Q4-23:In Section 3.(1)c, “Notification on Practical Operations of Electronic Study Data Submissions,” it states, “The use of SI units is recommended.” Please indicate the SI units that the PMDA considers acceptable, and any other points that should be considered when storing data in SI units.

Q4-24:For a clinical study with interim analyses, when is it necessary to submit the interim analysis data in addition to the final analysis data? Please indicate the format and method for submission, and the points to consider when the interim analysis data and the final analysis data are to be submitted together at the time of application.

Q4-25:In Section 2.(6) of the “Notification on Practical Operations of Electronic Study Data Submissions,” it states, “if the new drug application is to be made during a long-term study or based on the results of an interim analysis, the data from this clinical study submitted after the new drug application should include the data previously submitted at the time of the new drug application as well as the additional data.” If data from long-term continuous studies with different study numbers are compiled (e.g., in a case where subjects who completed the phase III study, Study No. 001, were enrolled in the continuous treatment study, Study No. 002, and the data from Study No. 001 and Study No. 002 are compiled. [Note that submission of data from the phase III study was already made at the time of application]), how will the folder name be specified for additional electronic data submission?

Q4-26:Is it possible to submit “specifications that show the analysis algorithm” in English?

Q4-27:Are there any issues to consider when multiple versions of CDISC standards, CDISC Controlled terminology, or external dictionaries are used in the same study?

Q4-28:Are there any points to consider when the CDISC Controlled Terminology version used to create the dataset and that used at validation are different?

Q4-29:The sponsor plans to code drugs with IDF, convert to WHO DDs data using Cross Reference Tool Japan (CRT Japan), and then store in SDTM. Is it possible to submit data with blanks in the variables except for drug information converted by CRT Japan?

Q4-30:A sponsor collects the adverse event terms in Japanese during the clinical study, creates the AE domain in both Japanese and English, and creates figures or tables based on the English dataset. In this case, is it possible to submit only the English dataset? In the meantime, what should the sponsor do if the figures or tables are created based on the Japanese dataset?

5. Questions on electronic study data on clinical pharmacology

Q5-1:Are all clinical pharmacology studies (including phase I studies) in the data package attached to a new drug application subject to electronic study data submission?

Q5-2:Please provide a more precise definition and explanation of “clinical studies where standard pharmacokinetic analysis was performed”.

Q5-3:In Question 12 of “Question and Answer Guide Regarding ‘Notification on Practical Operations of Electronic Study Data Submissions’”, what are “Individual clinical study data” in “clinical studies where standard pharmacokinetic analysis was performed”?

Q5-4:In the case of a population analysis being subject to submission, which data used to create the population analysis datasets—e.g., SDTM datasets, efficacy and safety analysis datasets of the clinical studies—are subject to submission?

Q5-5:In Section 3.(2)b(iii) of “Notification on Practical Operations of Electronic Study Data Submissions,” it states “Regarding data that were excluded from the analysis for reasons other than those specified in the analysis plan (for example, data excluded because they were determined to be outliers at the time of analysis), steps should be taken to clarify how the data were handled during the analyses, such as by flagging to identify them.” Is it possible to explain the handling of excluded data during the analysis by submitting the following two types of datasets: the final datasets (from which outliers, etc., were excluded) and whole datasets (including outliers, etc., with flagging to identify them).

Q5-6:When a sponsor conducts clinical trials to evaluate the effect of intrinsic or extrinsic factors such as age, sex, weight, genetic factors, severity of disease, disease complications, or dietary, alcohol or smoking habits on the pharmacokinetics of an investigational drug, are these study data subject to submission even if the study result indicates negative effect of these factors on the pharmacokinetics of the drug?

Q5-7:What indicates a “population analysis that provides a major evidence for dosage and administration” in Q10 of “Question and Answer Guide Regarding ‘Notification on Practical Operations of Electronic Study Data Submissions’”?

Q5-8:Please give some examples of “physiologically based pharmacokinetic model analysis that provides major evidence for dose adjustment because of drug interaction and for dosage and administration or dose adjustment,” in terms of the physiologically based pharmacokinetic model analysis (including simulations) in Q10 of “Question and Answer Guide Regarding ‘Notification on Practical Operations of Electronic Study Data Submissions’”.

Q5-9:When a sponsor submits results from all phase II and III studies (including long-term studies), which are generally regarded as the major evidence for evaluation of efficacy, safety, and dosage and administration [(2.2)a. Basic Principles on Electronic Submission of Study Data for New Drug Applications], is it necessary to submit data for clinical pharmacology analyses such as drug concentrations or the pharmacokinetic parameters included in these studies? If it is necessary, in what format should it be submitted?

Q5-10:Q12 of  “Question and Answer Guide Regarding ‘Notification on Practical Operations of Electronic Study Data Submissions’” states that ADaM is the preferable format for analysis datasets concerning PK or PK/PD analysis. In the case where a sponsor creates an analysis dataset in a format other than ADaM, and converts the dataset to ADaM for submission for a new drug application, is it necessary to submit the original dataset used for the analysis?

Q5-11:When a sponsor submits an analysis dataset for PK or PK/PD analysis of blood and urine concentration data, those data should be combined in one dataset?

Q5-12:Is it recommended that Analysis Results Metadata be submitted when a sponsor creates a dataset on clinical pharmacology studies in the CDISC standards format and submit the dataset? If yes, please show the scope of the Analysis Results Metadata subjected to submission.

Q5-13:As the pharmacokinetic parameters are derived data, and not the accrual data collected in clinical study, is it necessary to include the PP domain in the SDTM dataset?

Q5-14:When sponsor creates a PC domain and PP domain of SDTM dataset, is it necessary to create a RELREC dataset?

Q5-15:In the case where a PC domain is created by converting a dataset from a format other than CDISC standards, is it necessary to secure traceability by recalculating PK parameters from the data stored in the PC domain, and then storing the recalculated PK parameters into the PP domain?

Q5-16:In 3.(2)b.(i) “Notification on Practical Operations of Electronic Study Data Submissions”, it states that the analysis dataset for pharmacokinetic or pharmacokinetic/pharmacodynamic analysis of clinical studies where the standard pharmacokinetic analysis was performed should be submitted. In the case where only summary statistics of PK parameters are derived, is it necessary to submit the analysis dataset to output the summary statistics?

Q5-17: When a sponsor submits a standard pharmacokinetic analysis dataset in the ADaM format, what variables other than those that are required in ADaM IG should be included in the dataset?

Q5-18:Regarding “Population analysis, including simulations” in 3.(2)c.(ii) “Notification on Practical Operations of Electronic Study Data Submissions”, is it necessary to submit program or output files for covariate models or model evaluation so that it is possible to trace the series of processes used in establishing the final model?

Q5-19:Regarding “Population analysis, including simulations” in 3.(2)c.(ii) “Notification on Practical Operations of Electronic Study Data Submissions”, what kind of analysis output files are considered “files with the output of major results”? Is it necessary to submit the files even if the major results are described in the analysis report?

Q5-20: In 3.(2)c.(ii) “Notification on Practical Operations of Electronic Study Data Submissions”, it states, “If simulation was performed, submission of the program used for the simulation and program procedures is desirable.” Various simulations based on population analysis are conducted during drug development, which kinds of simulations are recommend to be submitted?

Q5-20-1:Regarding Q5-20, which kind of data should be submitted for each simulation? Is it necessary to submit programs used for Visual Predictive Check or datasets that are created for simulation?

Q5-20-2:According to Q5-20, qualitative evaluation with figures could be the basis for dose setting. In this case, is it necessary to submit the program used to create figure, or is it enough to submit only the simulation data that is the base of the figure?

Q5-21:Analysis results can be slightly different depending on the analysis software version. When confirming the results of analysis during the review, will reviewers always use the same software version the sponsor used to prepare the results? Is it necessary for sponsor to complete the analysis with the latest version of the software?

Q5-22:Have there been cases where the PMDA has sent inquiries after a new drug application because the reviewer had questions about the contents of submitted data or when the program doesn’t run in the PMDA’s environment?

Q5-23:When a program requires modifications in order to run at the PMDA, does the sponsor need to modify and resubmit the program?

Q5-24:Have there been cases where the PMDA requires sponsors to submit variables not used in the population analysis (including simulations)?

Q5-25:Please demonstrate how to store the dataset of integrated PK and PK/PD analysis and data for physiologically based pharmacokinetic model analysis.

Q5-26:When PK analyses are conducted at multiple time points in a single study, in which folder should ADaM datasets for each time point be stored?

Q5-27:Is there any particular format for the definition document for the analysis dataset for phase I and clinical pharmacology study results that are not based on CDISC standards and clinical pharmacology analyses? Is it possible to submit the definition document in English?

Q5-28:In the technical conformance guide 4.2.3.1, it is stated that if detailed information regarding analysis specifications on pharmacokinetics or pharmacokinetics/pharmacodynamics is included in documents such as the analysis plan, it is sufficient to submit only these documents. Is there a proper document in which such information can be stated?

Q5-29: Is it possible to submit attachment 5 of the technical conformance guide in English?
 

1. Questions on new drug review and consultation

Q1-6: In the technical conformance guide 3.6.1, it states, “Before transferring the electronic study data, the applicant should perform a validation, and necessary explanation should be given for any violations identified”. Is it permissible to provide the necessary explanation for violations at the Pre-NDA consultation?

A: Applicants are required to provide the necessary explanation for violations at the consultation on data format for the submission of electronic study data. At the Pre-NDA consultation, the PMDA will confirm only the scope of data to be submitted; they will not discuss the contents of the data. Therefore, consultation on the data format for the submission of electronic study data should be performed prior to the Pre-NDA consultation. Applicants should submit the Attachment 8, “Supporting Document on Consultation on Data Format of Submission of Electronic Study Data” reflecting the results of the consultation on the data format for the submission of electronic study data, when they apply for the Pre-NDA consultation. At the Pre-NDA consultation, the PMDA will confirm whether the results of the consultation on the data format for the submission of electronic study data correctly reflected. When the new drug application is submitted, the PMDA will check submitted data based on the Attachment 8, “Supporting Document on Consultation on Data Format of Submission of Electronic Study Data” that received at the Pre-NDA consultation.


Q1-6-1: If a sponsor cannot complete datasets or perform validation prior to the Pre-NDA consultation, what should they do?

A: Please consult with the PMDA at the Pre-NDA consultation. Even after Pre-NDA consultation, it will be necessary to provide explanations for violations of data format corresponding to technical conformance guide 3.6.1(b) if they are detected and the sponsor decides not to correct them.


Q1-16: When a sponsor performs validation with software that the vender claims is compatible with the software used by the PMDA, and then corrects data or explains the results, are there any particular points to consider?

A: When the PMDA also confirms a situation as described above, the PMDA will accept electronic study data and begin the review if there are no inadequacies in the FD application data, eCTD, or other documents. However, if violations corresponding to the technical conformance guide 3.6.1(a) and (b) are detected by validation at the PMDA, and there is no necessary explanation for the violations prior to the submission of study data, the PMDA will require correction of data or explanation regarding the cause of the violation and the reasons why it cannot be corrected.


Q1-17: If a detected violation is attributed to a bug of the validation software, is it necessary to correct the data?

A: When there is no obvious violation based on a check of actual datasets, even though a violation is detected by the validation software, the sponsor may give the rationale that the violation is caused by a bug in the validation software. Explain the rationale on Attachment 8, “Supporting Document on Consultation on Data Format of Submission of Electronic Study Data” and the data guide, and consult with the PMDA at the consultation on data format of the submission of electronic study data. When the validation software vender publishes the bug, the sponsor may point to it as the explanation.

 

3. Questions on electronic submission gateway

Q3-6: Will the PMDA perform validation of CDISC-conformant data when the applicant submits the electronic study data in response to inquiries?

A: Yes. The PMDA will apply the same concept of severity given in the validation rule shown in 3.6.1 of the technical conformance guide. Please submit the electronic study data via the “study data submission” window of the portal site when submitting the CDISC-conformant data in response to inquiries.
 

4. Questions on CDISC-conformant electronic study data


Q4-1: What is the base date for the “Date Support Begins (YYYY-MM-DD)” and the “Date Support Ends (YYYY-MM-DD)” in the PMDA Data Standards Catalog?


A: The base date is the submission date recorded by the applicant on the FD application of the new drug application form.


Q4-2: In the case where electronic study data is added or replaced during review, is it necessary to follow the standards with the same version number as those at the time of original submission?
If the “Date Support Ends” of the version used at the time of the original submission has already passed, what procedures should be followed?

A: Basically, it is necessary to use the same version as that used at the time of the original submission. To submit additional data to the previously submitted dataset, it is necessary to use the same version as that used for the original dataset.
However, on the following occasions where the application is submitted during the overlapping period, the applicant may submit new data using the newer version, as when there is:

  • Submission of a completely new set of study data
  • Submission of an entire set of previously submitted data along with additional data where both are created using the newer version of the standard

For details, see Figure 4-2.
Figure 4-2 Version of Standards


Q4-3:   Which files or contents will be included in the scope of CDISC-conformant validation performed by the PMDA?

A:   The PMDA performs validation on SDTM datasets, ADaM datasets, dataset definition documents, controlled terminologies and dictionaries. When the data written in Japanese (“Japanese data” in 4.1.5 of “Technical Conformance Guide on Electronic Study Data Submissions”) is submitted, no validation is performed on Japanese data and the validation is performed on the corresponding alphanumeric dataset.


Q4-4: When is it necessary to submit electronic datasets of integrated analyses (ISS/ISE)? What is the scope of electronic data on ISS/ISE that must be submitted?

A:   As explained in Section 1.(2) of “Notification on Practical Operations of Electronic Study Data Submissions,” submission of electronic data for ISS/ISE will be requested when integrated analyses of multiple clinical studies were performed for the assessment of specific efficacy or safety, such as assessments in special populations or of rare adverse events, and when the results are considered to be relevant to the assessment of efficacy, safety, and dosage and administration of the product. In order to confer with the PMDA on the scope of the submission of electronic data of integrated analyses, applicants must use the clinical trial consultation, not the “consultation on data format of submission of electronic study data,” because a decision on the scope of the submission accompanies scientific evaluations.
At the submission of data, definition documents and analysis programs (or program specifications) are required in addition to integrated analysis datasets. To confirm the details of such datasets, including file types to be submitted, etc., use “consultation on data format of submission of electronic study data.”



Q4-5: When is it necessary to submit electronic study data as attached documents in response to inquiries during a review? What is the scope of the electronic data that is subject to submission on such occasions?

A: In three cases, applicants must submit electronic study data as attached documents in response to inquiries during review:

  • When the study is ongoing at the time of application and additional electronic data will be submitted during review (e.g., when the application has been filed based on electronic study data from interim analyses or interim reports of a long-term study)
  • When an applicant makes important arguments (e.g., those affecting the main conclusions of efficacy and safety, considerations affecting prescriptions of dosage and administration or intended population) in the response to inquiries, and also when submission of analysis datasets used by the applicant are regarded as highly helpful for review
  • When electronic data of clinical studies or analyses that are important for evaluating efficacy, safety, and dosage and administration is not submitted at the time of application

These electronic study data should be submitted as attached documents in response to inquiries and/or revision of the eCTD. In any case, it is also required that applicants send documents amended for additionally submitted data (e.g., documents or analysis programs that should be submitted together with the datasets). For details regarding the necessity of these documents, etc., please consult with the review team.
As stated in Section 4.1.1.3 of “Technical Conformance Guide on Electronic Study Data Submissions,” it is not necessary to uniformly submit additional datasets for analyses that the applicant performed in response to inquiries.
For more detailed information on format and method for electronic study data submission, refer to Section 2.(5) and (6) of “Notification on Practical Operations of Electronic Study Data Submissions.” If any adjustment is necessary, such as the timing to submit additional electronic study data, etc., please consult with the review team.


 

Q4-6:If the protocol, etc., is prepared in Japanese, is it necessary to translate the information on the design of the clinical study into English, and store it in the SDTM Trial Design Model domain? Please indicate parameters and codes that the PMDA requests at a minimum for the TS domain of SDTM.

A: It is not likely that much information will be lost when Japanese data are translated into English for storing in the Trial Design Model. Therefore, when the protocol, etc., is prepared in Japanese, each piece of information must be stored in English after translation.
If SDTM datasets are prepared in accordance with SDTM IG v3.1.3 or later versions, it is necessary to include parameters classified into Required or Conditionally Required in the TS domain. If SDTM datasets are prepared in accordance with SDTM IG v3.1.2, include parameters that can be stored based on Section 7.6.2-4 of the SDTM IG. For parameters using controlled terminologies and ISO codes, store appropriate code values. For Registry Identifier, store registration numbers issued by CLINICALTRIALS.GOV, EUDRAC, JAPIC, etc. For parameters using UNII, NDF-RT, DUNS, or SNOMED CT, it is acceptable to store only code values available to the applicant. Table 4-6 shows the relationship between codes and parameters that use the codes other than controlled terminologies or ISO codes.

Table 4-6  Codes Corresponding to TS Domain Parameters and WEB Sites

TSPARMCD TSPARAM Code Website
CURTRT Current Therapy or Treatment UNII FDA Substance Registration System
http://fdasis.nlm.nih.gov/srs/srs.jsp
TRT Investigational Therapy or Treatment UNII FDA Substance Registration System
http://fdasis.nlm.nih.gov/srs/srs.jsp
PCLAS Pharmacological Class of Investigational Therapy NDF-RT NCI Term Browser
https://nciterms.nci.nih.gov/ncitbrowser/
pages/multiple_search.jsf
REGID Registry Identifier CLINICALTRIALS. GOV ClinicalTrials.gov
https://clinicaltrials.gov/
EUDRAC EU Clinical Trials Register
https://www.clinicaltrialsregister.eu/ctr-search/search
JAPIC JAPIC Clinical Trials Information
http://www.clinicaltrials.jp/user/
cteSearch.jsp
SPONSOR Clinical Study Sponsor DUNS TOKYO SHOKO RESEARCH
https://duns-number-jp.dnb.com/search/jpn/login.asp



Q4-7: In Section 3.(1)c of “Notification on Practical Operations of Electronic Study Data Submissions,” it states, “Use the WHO Drug Dictionaries Drug Code (WHO DDs) when coding drugs.” Please explain the background of the need to use WHO DDs, and give an example of how to store WHO DDs data under the CM domain of SDTM.

A: In order to promote international standardization of clinical study data, and to allow cross-sectional evaluations in the future, use of WHO DDs is required for electronic study data submission. It is possible to use sponsor-defined codes if no WHO DDs equivalent codes are identified; in this case, it will be necessary to specify in the data guide which sponsor-defined codes have been assigned to which variables.
Table 4-7 presents examples of how to assign WHO DDs codes to the CM domain of SDTM. It is also necessary to store WHO DDs ATC codes wherever possible. When multiple ATC codes exist, store them using the “Supplemental Qualifier special-purpose dataset.”

Table 4-7 Relationship between CM Domain and WHO DDs

Variable Name Variable Label WHO DDs
CMDECOD Standardized Medication Name WHO DDs Generic name
CMCLAS Medication Class WHO DDs ATC text
CMCLASCD Medication Class Code WHO DDs ATC code



Q4-8: In Section 3.(1)c of “Notification on Practical Operations of Electronic Study Data Submissions,” it states, “If data were collected in units that are commonly used where conversion of the data to those in SI units is possible, separately store the converted data in SI units in the SDTM dataset as data in the standard units and submit them.” Please indicate the scope of variables that need to be converted to SI units. Also, if data are collected in units other than SI units, how can the original data and the converted data be stored within the SDTM dataset?

A:   The use of SI units is required for all variables and parameters of test results to be stored in the Findings class domain of the SDTM dataset, as long as SI units are applicable.
When the original data and the converted data in SI units are stored together in the SDTM dataset, store the converted data into “--STRESC” (or “--STRESN” if necessary) and the original data into “--ORRES.” Also, in the data guide or dataset definition document, describe how each datum (original and converted) is stored, as well as the conversion equation.
In the case of multicenter or multiregional studies, etc., where different measurement units are used for capturing data by center or region, data in multiple units could be obtained for a single parameter (laboratory test). In such cases, it is possible to store data in uniform units other than SI units into “SUPP--” if necessary.

Examples of how to store data in conventional units and SI units into SDTM
[Example 1] When values in domestically conventional units and internationally conventional units both exist:
Store values in domestically conventional units under “--ORRES” and values in internationally conventional units under “SUPP--.” Store SI values under “--STRESC” (or “--STRESN” if necessary).
[Example 2] When central clinical laboratory values and in-hospital clinical laboratory values both exist:
Store central values under “--ORRES” and in-hospital values under “SUPP--.” Store SI values under “--STRESC” (or “--STRESN” if necessary) after unifying them into a single unit per parameter and then converting.


Q4-9: Some values need to be displayed in Japanese on analysis results, and such values need to be stored in datasets in Japanese. In such cases, should only datasets with alphanumeric values be separately prepared for electronic study data submission?

A: Basically, it is only necessary to submit datasets with alphanumeric values for electronic study data submission. For variables that can be properly translated (from those displayed in Japanese analysis results into English) without loss of information, it is acceptable to store the translated variables in datasets, and to submit only the datasets with alphanumeric values. In such cases, it is possible, in addition to the datasets with alphanumeric values, to submit together the original datasets with Japanese characters that were used for displaying analysis results instead of alphanumeric values, from the viewpoint of traceability between the original and translated datasets or to present reference materials. If certain information is likely to be lost when Japanese data is translated into English, follow Section 4.1.5 of “Technical Conformance Guide on Electronic Study Data Submissions” for submission. In the case of datasets translated at the time of their creation, this should be described in the data guide.


Q4-10: If datasets include languages other than English or Japanese, what procedures should be followed?

A: Basically, the requirement is that submitted datasets be entirely translated into English. However, the need to translate specific variables into English may depend on the level of importance of the relevant variables; thus, use the “consultation on data format of submission of electronic study data” for each case if needed. In the event that datasets are translated, this should be described in the data guide.


Q4-11: When translation is performed (e.g., from Japanese to English), is it necessary to certify the correctness of the translation?

A: No written form is required, but the applicant is responsible for ensuring the accuracy of the translation.


Q4-12: When Japanese datasets will be submitted in addition to alphanumeric datasets, is it necessary to create a dataset definition document for each dataset?

A: The definition document is needed only for the alphanumeric datasets. Please store the definition document in the same folder as the alphanumeric datasets.


Q4-13: If analysis software is used that requires no explicit program creation, is it permissible to submit an operational log instead of a program? Or will “the submission of specifications that show the analysis algorithm” be separately requested? Please indicate examples of the contents to be described in the “specifications that show the analysis algorithm.”

A: Submission of an operational log will be sufficient instead of the program, if the log clarifies the analysis algorithm. In the event that the operational log is unlikely to clarify the analysis algorithm, as in the case where “submission of the program itself is difficult,” then “the submission of specifications that show the analysis algorithm” will also be needed. In the “specifications that show the analysis algorithm,” please specify datasets and variables to be analyzed, and details of analytical methods.


Q4-14: If datasets in a format other than the CDISC standards are converted into a CDISC-conformant format for submission, and if the source datasets and the Annotated CRF are to be submitted together as an explanation of traceability, under which folder should they be stored?

A: Store the source datasets (which means the datasets before conversion into a CDISC-conformant format), the explanation of traceability, and the accompanying files under the “legacy” folder.


Q4-15: When submitting electronic data of an integrated analysis (ISS/ISE), in which folder should they be stored?

A: Basically, we expect that data from multiple studies subject to an integrated analysis will be combined into a single dataset, and that one analysis dataset will be submitted for each analysis. When datasets from multiple studies are consolidated by a program for analysis, it is possible to submit the datasets of each study and the program containing the process of consolidation. Regardless of whether or not datasets are integrated, store datasets for the integrated analysis within the “iss/ise” folder, which allows the folder name to be consistent with that including CSR in eCTD.


Q4-16: When submission of the analysis program is difficult, submission of the “specifications that show the analysis algorithm” may be considered. In which folder should they be stored?

A: Store the analysis specifications in the “programs” folder. This should be explained in the data guide.


Q4-17: In order to explain the process by which the variables of ADaM datasets were created, reference data used to create ADaM datasets (reference tables such as Lookup tables, Metadata, etc.) are to be submitted; in which folder should they be stored?

A: Store them in the “misc” folder. If an applicant submits programs used to create ADaM datasets and the reference data mentioned above is used in the program, it is also possible to store the reference data in the “programs” folder. This should be explained in the data guide.


Q4-18: Data used to impute missing data (e.g., multiple imputation) are to be submitted as an ADaM data source; in which folder should they be stored?

A: Store them in the “misc” folder. The handling of missing data should be explained in the dataset definition document and in the data guide.


Q4-19: In Section 4.1.1.4 of the “Technical Conformance Guide on Electronic Study Data Submissions,” it states, “the character sets and the encoding system used to create the dataset should be described in the data guide;” please give specific examples of the character sets and encoding system that must be described.

A: Information on the character sets and the encoding system is needed to identify the characters intended by the dataset creator.
Examples of character set information to be described in the data guide:
[Character set] JISX0208                   [Encoding system] Shift-JIS
[Character set] JISX0208                   [Encoding system] EUC-JP
[Character set] UNICODE (USC-2)    [Encoding system] UTF-8


Q4-19-1: In connection with Q4-19 above, how can information be obtained on the encoding system used?

A: In principle, encoding system-related information can be obtained from the property of the dataset. In the case of an unconventional encoding system used for relevant character sets, provision of detailed data may be additionally requested.


Q4-19-2: As shown in one of the examples in Q4-19 above, when the encoding system is UTF-8, is it necessary to include further information such as USC-2 for the character set, UNICODE?

A: No further information is necessary. However, if the given character set-related information does not work, additional detailed information may be requested.


Q4-20: If the application is to be made based on the results of an interim analysis, is it permissible to include data obtained after the cutoff of the interim analysis up to the time of application with data submitted for the application?

A: If the application is to be made based on the results of an interim analysis, it is required that data up to the cutoff of the interim analysis be included in the electronic data submission; it is also acceptable, however, to include data after the cutoff. For instance, if the application is made after a certain period of time from the interim analysis, it may be useful to include data after the interim analysis. If the application is made including data after the interim analysis, clearly distinguish data before and after the cutoff, and the handling of the relevant data must be explained in the data guide.


Q4-21: Is there anything special to consider when the SDTM IG v3.1.2 Amendment is used for the creation of the SDTM datasets?

A: Put “SDTM-IG 3.1.3” for the version of SDTM IG on the dataset definition document. Otherwise, validation of CDISC-conformant datasets will not be performed properly at the PMDA.


Q4-22: Is it possible to store and submit the datasets/files not conforming to CDISC in the folder that is defined to store SDTM datasets or ADaM datasets?

A: Within the folder storing SDTM datasets or ADaM datasets, it is possible to store datasets in the SAS XPORT format conforming to the CDISC standards, together with the accompanying definition documents in the XML format, style sheets, and PDF documents. Do not store csv files, XML files other than definition documents, or SAS XPORT datasets not conforming to the CDISC standards.


Q4-23: In Section 3.(1)c, “Notification on Practical Operations of Electronic Study Data Submissions,” it states, “The use of SI units is recommended.” Please indicate the SI units that the PMDA considers acceptable, and any other points that should be considered when storing data in SI units.

A: Currently, the PMDA considers the use of SI units, non-SI units that are accepted for use with SI units, and SI prefixes listed in published BIPM (Bureau International des Poids et Mesures) brochure as acceptable use of the SI units. Prefixes should be used to keep numbers in the range of 0.1–1000.


Q4-24: For a clinical study with interim analyses, when is it necessary to submit the interim analysis data in addition to the final analysis data? Please indicate the format and method for submission, and the points to consider when the interim analysis data and the final analysis data are to be submitted together at the time of application.

A: In a clinical study subject to electronic data submission, if a decision is made regarding discontinuation/continuation of the study, the need for an important study design amendment or the contents of the amendment, etc., based on the interim analysis results, applicants may be asked to submit the analysis datasets used for the interim analysis in addition to the final analysis data (or data at the final cutoff used for the application) at the time of application. If analysis datasets and analysis programs used for the interim analysis are to be submitted, store them with the dataset definition document in the “misc” folder. It must be mentioned in Attachment 8, “Supporting Document on Consultation on Data Format of Submission of Electronic Study Data” to the “Notification of Implementation Outline of Consultation and Confirmatory Investigation, etc.,” and in the data guide that the analysis datasets used for the interim analysis are to be submitted. If no SDTM is created exclusively for the interim analysis, submission of SDTM for the interim analysis will not be necessary. Use the clinical trial consultation to verify the necessity of electronic data submission of the interim analysis datasets and the scope of submission.


Q4-25: In Section 2.(6) of the “Notification on Practical Operations of Electronic Study Data Submissions,” it states, “if the new drug application is to be made during a long-term study or based on the results of an interim analysis, the data from this clinical study submitted after the new drug application should include the data previously submitted at the time of the new drug application as well as the additional data.” If data from long-term continuous studies with different study numbers are compiled (e.g., in a case where subjects who completed the phase III study, Study No. 001, were enrolled in the continuous treatment study, Study No. 002, and the data from Study No. 001 and Study No. 002 are compiled. [Note that submission of data from the phase III study was already made at the time of application]), how will the folder name be specified for additional electronic data submission?

A: Under the circumstances described above (to submit additional electronic data after the application), store the additional data (Study No. 001 and 002 combined) in the folder for Study No. 002 submission. For the methods and procedures of submission of CDISC-conformant datasets after the application, refer to the Answer to Q3-20.
For combined data from multiple studies, it will be necessary to specify in the dataset which study each data comes from. The data guide must include points to consider, such as the fact that there is an additional submission of compiled data from multiple studies, the method for compiling data, and the presence/absence in the additional data of new subjects from the continuous treatment study. For details regarding methods for data compilation and submission, utilize “consultation on data format of submission of electronic study data” as needed.

 

Q4-26: Is it possible to submit “specifications that show the analysis algorithm” in English?

A: Yes.
 

Q4-27: Are there any issues to consider when multiple versions of CDISC standards, CDISC Controlled terminology, or external dictionaries are used in the same study?

A: In the “Notification on Practical Operations of Electronic Study Data Submissions”, it states that, “a single version of the standards must be used within a clinical study. If different versions of the standard were used within the same clinical study, this situation and the reason for it must be explained in the data guide.” At the PMDA, validation of study data will be conducted in the Gateway system based on the single CDISC standards version stated in the define.xml and single CDISC Controlled terminology version entered in the Gateway system. Applicants should also perform validation of study data based on the single CDISC standards version in the define.xml and single CDISC Controlled terminology version in the Gateway system, and correct study data or explain errors based on the results. Applicants should also specify all versions of CDISC standards, CDISC Controlled terminology, or external dictionaries used for the creation of datasets and for validation of study data in Attachment 8, “Supporting Document on Consultation on Data Format of Submission of Electronic Study Data”.


Q4-28: Are there any points to consider when the CDISC Controlled Terminology version used to create the dataset and that used at validation are different?

A: In the Gateway system, enter the CDISC Controlled Terminology version used at validation. In Attachment 8, “Supporting Document on Consultation on Data Format of Submission of Electronic Study Data”, specify the versions of CDISC Controlled terminology used to create datasets and at validation. It is necessary to explain in the data guide if the CDISC Controlled Terminology version used to create datasets and the version used at validation are different, and to specify each.


Q4-29: The sponsor plans to code drugs with IDF, convert to WHO DDs data using Cross Reference Tool Japan (CRT Japan), and then store in SDTM. Is it possible to submit data with blanks in the variables except for drug information converted by CRT Japan?

A: If an applicant stores information such as drug names that cannot be converted by CRT Japan to the dataset, it is possible to submit only data that is converted by CRT Japan in the SDTM dataset.


Q4-30: A sponsor collects the adverse event terms in Japanese during the clinical study, creates the AE domain in both Japanese and English, and creates figures or tables based on the English dataset. In this case, is it possible to submit only the English dataset? In the meantime, what should the sponsor do if the figures or tables are created based on the Japanese dataset?

A: In both cases, it is possible to submit only the English dataset if all information on the Japanese dataset is included in the English dataset. It is also possible to submit the Japanese dataset along with the English dataset.
 

5. Questions on electronic study data on clinical pharmacology

Q5-1: Are all clinical pharmacology studies (including phase I studies) in the data package attached to a new drug application subject to electronic study data submission?

A: Electronic study data from studies listed in Question 10 of “Question and Answer Guide Regarding ‘Notification on Practical Operations of Electronic Study Data Submissions’” are subject to submission. For clinical pharmacology studies (including phase I studies) that provide major evidence for dosage and administration or dose adjustment, electronic data must be submitted. Only data from clinical pharmacology studies that provide “major evidence for dosage and administration” are subject to submission; thus, not all clinical pharmacology studies are considered subject to submission. To ensure the need for electronic submission of study data, it is recommended that applicants use the clinical trial consultation.


Q5-2: Please provide a more precise definition and explanation of “clinical studies where standard pharmacokinetic analysis was performed”.

A: These are clinical studies where the pharmacokinetics of a drug was evaluated using the method defined as a standard pharmacokinetic study in the “Clinical Pharmacokinetic Studies of Pharmaceuticals” announced on 1 June 2001 by the Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour, and Welfare.


Q5-3: In Question 12 of “Question and Answer Guide Regarding ‘Notification on Practical Operations of Electronic Study Data Submissions’”, what are “Individual clinical study data” in “clinical studies where standard pharmacokinetic analysis was performed”?

A: They involve not only domains related to pharmacokinetic or pharmacokinetic/pharmacodynamic analyses but also all SDTM datasets of the clinical studies subject to submission.


Q5-4: In the case of a population analysis being subject to submission, which data used to create the population analysis datasets - e.g., SDTM datasets, efficacy and safety analysis datasets of the clinical studies - are subject to submission?

A: For a population analysis, only electronic data related to the population analysis (such as analysis datasets for the population analysis) are subject to submission. In the case where clinical studies used for creation of population analysis datasets are inconsistent with studies that must be electronically submitted, as listed in Section 2(2) of “Basic Principles on Electronic Submission of Study Data for New Drug Applications,” it is unnecessary to submit the SDTM datasets and efficacy and safety analysis datasets of the clinical studies from which data was drawn.


Q5-5: In Section 3.(2)b(iii) of “Notification on Practical Operations of Electronic Study Data Submissions,” it states “Regarding data that were excluded from the analysis for reasons other than those specified in the analysis plan (for example, data excluded because they were determined to be outliers at the time of analysis), steps should be taken to clarify how the data were handled during the analyses, such as by flagging to identify them.” Is it possible to explain the handling of excluded data during the analysis by submitting the following two types of datasets: the final datasets (from which outliers, etc., were excluded) and whole datasets (including outliers, etc., with flagging to identify them).

A: Yes, it is possible. The above statement in the Notification means that it is necessary to submit datasets in a manner that clarifies why data was excluded from analyses; thus, submission can be made in other ways as long as it fulfills this aim.


Q5-6: When a sponsor conducts clinical trials to evaluate the effect of intrinsic or extrinsic factors such as age, sex, weight, genetic factors, severity of disease, disease complications, or dietary, alcohol or smoking habits on the pharmacokinetics of an investigational drug, are these study data subject to submission even if the study result indicates negative effect of these factors on the pharmacokinetics of the drug?

A: It is not necessary to submit study data in that case. The 0.8–1.25 range on the geometric mean ratio of pharmacokinetic parameters (when pharmacokinetic parameters are log-normally distributed) can be used as one of the criteria for assessing a “negative effect” in deciding whether the study data need to be submitted. In some cases, study data might not need to be submitted even though the ratio is not within the range of 0.8–1.25. To ensure the necessity of submission of study data evaluating the effect of intrinsic or extrinsic factors, we recommend using a clinical trial consultation if necessary.


Q5-7: What indicates a “population analysis that provides a major evidence for dosage and administration” in Q10 of “Question and Answer Guide Regarding ‘Notification on Practical Operations of Electronic Study Data Submissions’”?

A: This refers to population analysis that includes data from a phase 3 trial, or which is the basis of dosage in a phase 3 trial. Such analyses are generally considered to be subject to submission.
 

Q5-8: Please give some examples of “physiologically based pharmacokinetic model analysis that provides major evidence for dose adjustment because of drug interaction and for dosage and administration or dose adjustment,” in terms of the physiologically based pharmacokinetic model analysis (including simulations) in Q10 of “Question and Answer Guide Regarding ‘Notification on Practical Operations of Electronic Study Data Submissions’”.

A: Examples include the results of an analysis used as the basis of the content in the section on drug interactions (contraindication or caution for combination) in a package insert, or used as the basis of the judgment not to conduct a clinical drug interaction study.


Q5-9: When a sponsor submits results from all phase II and III studies (including long-term studies), which are generally regarded as the major evidence for evaluation of efficacy, safety, and dosage and administration [(2.2)a. Basic Principles on Electronic Submission of Study Data for New Drug Applications], is it necessary to submit data for clinical pharmacology analyses such as drug concentrations or the pharmacokinetic parameters included in these studies? If it is necessary, in what format should it be submitted?

A: It is necessary to submit the data for clinical pharmacology analyses included in the clinical studies shown above. Please submit data following the data standards shown in 3.(2)a of “Notification on Practical Operations of Electronic Study Data Submissions”, and submit programs or analysis specifications based on “Notification on Practical Operations of Electronic Study Data Submissions” and the technical conformance guide. 

 
Q5-10: Q12 of “Question and Answer Guide Regarding ‘Notification on Practical Operations of Electronic Study Data Submissions’” states that ADaM is the preferable format for analysis datasets concerning PK or PK/PD analysis. In the case where a sponsor creates an analysis dataset in a format other than ADaM, and converts the dataset to ADaM for submission for a new drug application, is it necessary to submit the original dataset used for the analysis?

A: No, it is not necessary to submit the original dataset used for the analysis. In cases where the original dataset is considered useful for explaining traceability between datasets or to show analysis specifications, it may be submitted and used for the explanation.
 

Q5-11: When a sponsor submits an analysis dataset for PK or PK/PD analysis of blood and urine concentration data, those data should be combined in one dataset?

A: Either a single or separate datasets is acceptable for submission if the dataset can be used for analysis without additional handling (so called Analysis Ready).

 
Q5-12: Is it recommended that Analysis Results Metadata be submitted when a sponsor creates a dataset on clinical pharmacology studies in the CDISC standards format and submit the dataset? If yes, please show the scope of the Analysis Results Metadata subjected to submission.

A: Even for clinical pharmacology studies, submission of the Analysis Results Metadata for the analyses performed to obtain the main results of the clinical study is recommended if the dataset was created in CDISC standards format in those studies.

 
Q5-13: As the pharmacokinetic parameters are derived data, and not the accrual data collected in clinical study, is it necessary to include the PP domain in the SDTM dataset?

A: The pharmacokinetic parameters themselves are considered as data to capture the characteristics of the drug and should be included in database. Therefore, please submit the SDTM dataset with the PP domain.

 
Q5-14: When sponsor creates a PC domain and PP domain of SDTM dataset, is it necessary to create a RELREC dataset?

A: Creating a RELREC dataset would be preferable, but explaining the procedures by which the variables in the PP domain were created from the variables in the PC domain in a document such as a data guide would be also acceptable, if the logic needed to create a RELREC dataset were too complex.

 
Q5-15: In the case where a PC domain is created by converting a dataset from a format other than CDISC standards, is it necessary to secure traceability by recalculating PK parameters from the data stored in the PC domain, and then storing the recalculated PK parameters into the PP domain?

A: In that case, the PK parameters stored in the PP domain will not need to be recalculated from the PC domain. However, please explain the relationship between information in the PC and PP domains (the process used to create the PC and PP domains. relationship between variables in these domains, etc.) in the data guide.

 
Q5-16: In 3.(2)b.(i) “Notification on Practical Operations of Electronic Study Data Submissions”, it states that the analysis dataset for pharmacokinetic or pharmacokinetic/pharmacodynamic analysis of clinical studies where the standard pharmacokinetic analysis was performed should be submitted. In the case where only summary statistics of PK parameters are derived, is it necessary to submit the analysis dataset to output the summary statistics?

A: No, it is not necessary to submit the analysis dataset in that case.
 

Q5-17: When a sponsor submits a standard pharmacokinetic analysis dataset in the ADaM format, what variables other than those that are required in ADaM IG should be included in the dataset?

A: Please include the variables necessary for the analysis, and which can be used for analysis without any additional data handling, as well as the variables that are required in the ADaM IG. For example, derived values needed for the analysis such as AUC used as a PK index, the change in a PD marker from baseline, and flags to extract records for analysis should be included in the dataset.

 
Q5-18: Regarding “Population analysis, including simulations” in 3.(2)c.(ii) “Notification on Practical Operations of Electronic Study Data Submissions”, is it necessary to submit program or output files for covariate models or model evaluation so that it is possible to trace the series of processes used in establishing the final model?

A: As the basic model and final model represent the basic scope of submissions, it is not necessary to submit program or output files for covariate models or model evaluation. However, if the process of covariate models or model evaluation is complicated, and the sponsor considers that such files would aid understanding of the analysis method, it is possible to submit these files.
 

Q5-19: Regarding “Population analysis, including simulations” in 3.(2)c.(ii) “Notification on Practical Operations of Electronic Study Data Submissions”, what kind of analysis output files are considered “files with the output of major results”? Is it necessary to submit the files even if the major results are described in the analysis report?

A: The files in question are output files with calculated values by the base model or the final model. If major results are written in the analysis report, it is not necessary to submit the output files, but this should be mentioned and explained in the data guide.
 
 
Q5-20: In 3.(2)c.(ii) “Notification on Practical Operations of Electronic Study Data Submissions”, it states, “If simulation was performed, submission of the program used for the simulation and program procedures is desirable.” Various simulations based on population analysis are conducted during drug development, which kinds of simulations are recommend to be submitted?

A: Simulations used for decision-making are recommend to be submitted, for example, determination of the patient population to be administrated, or the dosage.

 
Q5-20-1: Regarding Q5-20, which kind of data should be submitted for each simulation? Is it necessary to submit programs used for Visual Predictive Check or datasets that are created for simulation?

A: Programs that can reproduce the results (or specifications that demonstrate the analysis algorithm if it is difficult to submit the program itself) and program procedures are within the scope of submission. It is not necessary to submit data regarding simulation for model evaluation (such as Visual Predictive Check) or datasets created in a series of simulation processes.

 
Q5-20-2: According to Q5-20, qualitative evaluation with figures could be the basis for dose setting. In this case, is it necessary to submit the program used to create figure, or is it enough to submit only the simulation data that is the base of the figure?

A: When dose setting is conducted based on a figure that shows the simulation results visually, please submit the program used to create the figure. If it is difficult to submit the program used, submission of specifications that demonstrate the analysis algorithm would be sufficient, as shown in 3.(2)c.(ii) “Notification on Practical Operations of Electronic Study Data Submissions”.

 
Q5-21: Analysis results can be slightly different depending on the analysis software version. When confirming the results of analysis during the review, will reviewers always use the same software version the sponsor used to prepare the results? Is it necessary for sponsor to complete the analysis with the latest version of the software?

A: It is preferable for the PMDA to analyze in the same environment as the sponsor, but it is not realistic for to assume this will always be the case. Therefore, in some cases, the PMDA analysis will be conducted using a different software or version, with the understanding that analysis results would be slightly different depending on the environment. The sponsor does not necessarily need to use the latest version of the software.

 
Q5-22: Have there been cases where the PMDA has sent inquiries after a new drug application because the reviewer had questions about the contents of submitted data or when the program doesn’t run in the PMDA’s environment?

A: Basically, the PMDA will not send inquiries regarding the contents of programs or data. Please record details such as definition files, analysis specifications, and program procedures in each briefing document.

 
Q5-23: When a program requires modifications in order to run at the PMDA, does the sponsor need to modify and resubmit the program?

A: No, that will not be necessary.
 

Q5-24: Have there been cases where the PMDA requires sponsors to submit variables not used in the population analysis (including simulations)?

A: In general, the PMDA won’t require the creation and submission of a dataset with new variables after a new drug application. On the other hand, at the clinical consultation, the PMDA can propose the creation of a dataset with new variables (e.g., age, when considering dose setting in children).


Q5-25: Please demonstrate how to store the dataset of integrated PK and PK/PD analysis and data for physiologically based pharmacokinetic model analysis.

A: Create a [study id/iss/ise] folder with the same name of the folder in the CTD Module 5, and create the folder for analysis under the [study id/iss/ise] folder, then store data in the folder for analysis.

 
Q5-26: When PK analyses are conducted at multiple time points in a single study, in which folder should ADaM datasets for each time point be stored?

A: If timing of analysis for efficacy and safety and analysis is different from that for PK (e.g., [1] multiple PK analyses are conducted during the study period where a single analysis for efficacy and safety is conducted, or [2] the timing of PK data collection is different from that of efficacy and safety), change the ADaM dataset file names based on analysis timing, and store them in [study id/iss/ise]¥analysis¥adam¥datasets folder. When the method above is difficult to apply, or when there are multiple time points to analyze as a whole study (i.e., when interim analysis is conducted and submitted with the final analysis), store the most important ADaM dataset for evaluation in [study id/iss/ise]¥analysis¥adam¥datasets folder, and store other datasets in the “misc” folder. If a sponsor needs to discuss which time point should be considered the most important for evaluation, or whether analyses at each time point should be submitted, please use clinical consultations. If the sponsor needs to discuss how to store data, please use “consultation on data format of submission of electronic study data”.

 
Q5-27: Is there any particular format for the definition document for the analysis dataset for phase I and clinical pharmacology study results that are not based on CDISC standards and clinical pharmacology analyses? Is it possible to submit the definition document in English?

A: There is no particular format, and it is possible to submit the definition document created by the sponsor without any changes. It is also possible to submit the definition document in English.
 

Q5-28: In the technical conformance guide 4.2.3.1, it is stated that if detailed information regarding analysis specifications on pharmacokinetics or pharmacokinetics/pharmacodynamics is included in documents such as the analysis plan, it is sufficient to submit only these documents. Is there a proper document in which such information can be stated?

A: Please include the information in the document submitted for new drug applications, such as Analysis specifications. In the Pre-NDA consultation and consultation on data format of submission of electronic study data, please include it on Attachment 8, “Supporting Document on Consultation on Data Format of Submission of Electronic Study Data”.


Q5-29: Is it possible to submit attachment 5 of the technical conformance guide in English?

A: Yes, it is possible.
 

Notice:This English version of the Japanese FAQs is provided for reference purposes only. In the event of any inconsistency between the Japanese original and the English translation, the former shall prevail.

 

6. FAQs on Electronic Study Data Submission (in Japanese)

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