memnRegulated Product Submission Topic
Not Balloting this Cycle
HL7 RPS, R2
HL7 Version 3 Standard: Regulated Product Submission, Release 2
Normative Ballot 2 - September 2014
Not Balloting This Cycle
HL7 IG RPS, R2
HL7 Version 3 Implementation Guide: Regulated Product Submission, Release 2
Last Ballot: Informative Ballot 1 - September 2013

Content Last Edited: 2017-03-27T01:53:01


Overview

Regulatory Authorities (hereinafter referred to as Regulators) exchange information with the regulated industry (hereinafter referred to as Industry) and each other to address a variety of regulatory issues. The information included in these regulatory exchanges can be provided in paper or electronically in the form of digital files. Frequently, the new information is directly related to information previously provided. Because information is submitted over time, often in increments, it is difficult to efficiently process and review the new information in light of pre-existing information.

The goal of the Regulated Product Submission message is to facilitate the processing and review of electronic regulatory submissions. Accordingly, the Regulated Product Submission Refined Message Information Model (RPS RMIM) captures all information required for the efficient processing and review of electronic regulatory submissions.

Different regulated product types (e.g., devices, medicinal products) specify different hierarchical constructs (i.e., tables of contents) to organize the information provided in the regulatory exchanges. However, the basic requirements for submitting information electronically over time are the same. Therefore, the objective of the Regulated Product Submission message is to define one message structure that can be used for all regulated products. The message standard is intended to be used worldwide, to support the review of regulated products including, but not limited to, foods, medical devices, human therapeutics, and veterinary medicines. It is important to note that the wide range of products that is contemplated leads to providing a generic structure for the actual specification.

Release 2 Normative

Further changes and scope adjustments (e.g., addition of International Conference on Harmonisation (ICH) and International Medical Device Regulators Forum (IMDRF) requirements) have been made to the Regulated Product Submission (RPS) standard during and after the RPS Release 2 DSTU.

In addition to the inclusion of the ICH requirements, this release includes enhancements to support:

  • European procedure types and modes and the recent European Variation legislation changes.
  • Japanese health authority (PMDA) requirements for Japanese specific hierarchical concept of a submission in the RPS concepts of Application and Submission, and the ability to define and reuse documents.
  • The definition of product has been reduced to a set of essential components and a product category has been added to further support Japanese review procedures.

Changes in Release 2 normative

Release 2 normative includes the following major changes since its last ballot:

  • Document.component was removed - i.e., compound document
  • RelatedDocument was removed
  • Document setId and versionNumber was removed - i.e., the document does not have a life cycle
  • Context of Use Title, setId and versionNumber were removed - i.e., life cycle operations will be based solely on the use of the replacementOf.RelatedContextOfUse
  • ReviewableUnit was removed and all associated act relationships
  • PreviousKeywordDefinition was removed
  • RegulatoryStatus was added to Review

Scope

The scope of the standard is to define the message for exchanging information electronically between Regulators and Industry, and between sets of regulators. The message provides the ability to describe the contents of the regulatory exchange and all information needed to process the exchange between parties. This message is designed to be flexible enough to be used to support regulatory exchanges for any regulated product.

The requirements are represented in the storyboards to follow, which represent various regulatory product submissions. Typically an application will consist of multiple submissions and regulatory assessments over a period of time. For example, the marketing application for a drug or device can generate multiple regulatory decisions. The first decision may support the initial marketing approval of the product for a specific indication. Subsequent regulatory decisions may approve or deny additional indications or product changes. The application thus contains multiple submissions, each with their own regulatory action. Each of those submissions (e.g., initial marketing application, supplemental marketing application) would generally be comprised of multiple submissions units.

The storyboards below are organized by the interactions that are typically seen between Industry and the Regulators.

The Regulated Clinical Research Information Management Technical Committee invites anyone with additional requirements to submit content proposals for future releases of the standard.

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 Storyboards (Sorted by Title)
 Storyboards (Sorted by Display Order)
 
pointer Submission Review Request (PORP_ST000001UV
pointer Submission Content Response (PORP_ST000002UV
pointer Additional Information (PORP_ST000003UV
pointer Regulatory Action Response (PORP_ST000004UV
pointer Managing content across multiple submission units (PORP_ST000005UV
Reference

For details on the interpretation of this section, see the storyboard discussion in the Version 3 Guide.

Purpose

The submission review request is initiated by an applicant/sponsor. It provides information to the Regulator about a regulatory activity and requests that a regulatory review be undertaken. This scope of submission review requests are just the initial request and will be followed by additional information over time - see the Additional Information storyboards.

Diagram
Activity Diagram
Interaction List
Submission Unit sent Schema View PORP_IN000001UV
Narrative Example

Acme Pharmaceuticals has prepared information relating to its new product - Global Fixit. This information provides information about the quality, safety and effectiveness of the product, and consists of many files that Acme has collected over several years. Acme has marshaled these files, which are designed to address a previously defined set of categories, into its first submission unit. That first submission unit will be sent to a regulator for marketing approval in that jurisdiction. In this initial submission unit, message identifies all of the submitted documentation, and indicates the category or categories to which the documentation belongs. This first submission unit commences the application and represents the first regulatory submission for that application.

Since this is the initial submission unit for the application, each use of a document in this submission unit is active. The submission is then transmitted to the regulator.

The regulator receives the submission and validates the message for accuracy. The regulator incorporates the message into their tracking/review system creating a new application, original submission, and the first submission unit to the original submission.

Narrative Example

Device Co. is planning on creating a submission for a Class III product. Device Co. has already received approval of the original submission i.e., the original submission unit and its amendments.

This product is going to be used for a different purpose than stated in the original submission so a new Submission must be initiated. Device Co will submit the new submission and supporting documentation containing the relevant information that supports the new use of the product. As required by Regulators, this new submission and the original submission will be linked together under the same application.

The Regulator receives and validates this submission unit for this new submission. This new submission (referred to as a supplement or variation) and the original submission are both associated to the same application.

Note:In most cases, supplements/variations can only be created after the original has been approved.

Narrative Example

In certain regulatory processes, the same documentation may need to be submitted to multiple applications.

Acme Manufacturing produces an annual report that pertains to multiple active applications. The company submits one submission unit and applies that unit to each application that requires the annual report. The Regulator processes this submission unit as a new Submission and associates it to all relevant applications.

Narrative Example

In certain regulatory processes, the same documentation may need to be submitted to multiple submissions.

Acme Manufacturing changes some CMC processes that pertain to multiple active submissions for a product. The company submits one CMC submission unit and applies that unit to each submission that it pertains to. The Regulator processes this submission unit and associates it to all relevant submissions.

Narrative Example

The European manufacturer, who produces the Calming Myst product, has done previous business with Acme manufacturing for a number of years. In a previous application - for Calming Balm - Acme had submitted information for that manufacturer that is relevant to the Calming Myst application. Since the Regulator already has the documents for the manufacturer, Acme decides to reference those documents in the new application. The Calming Myst submission unit contains references to those previously submitted information. The submission unit does not contain copies of the previously submitted information. The Regulator processes this submission unit. It is possible for the reviewers to access the referenced documents as if they had been submitted in this submission unit.

Narrative Example

Device Company ABC submits the first of three modules of a modular Premarket Approval (PMA) to the FDA/CDRH for Product Implant 123, including the contact information for the submission (e.g., any points of contact first name and last name, type of contact, address, phone, email, fax), regulator information (i.e., Agency, Center), submission information (e.g., regulator submission number, , submission unit type (e.g., category = 'New' and sub category = "Amendment" or "Supplement") and Comment field (free text description).

On receipt of the submission unit, the regulator processes the information and is now ready for review. If there are any questions on the submission unit, the receiver uses the contact information appropriately.

Narrative Example

Acme Pharmaceuticals has prepared information relating to its new product - Global Fixit. This information provides information about the quality, safety and effectiveness of the product, and consists of many files that Acme has collected over several years. Acme has collated these files, which are designed to address a previously defined set of categories, into its first submission unit. The first submission unit will be sent to multiple regulatory authorities within Europe for marketing approval through the Decentralised Procedure. One country will be defined and act as Reference Member State (RMS) and the others will be defined and act as Concerned Member States (CMSs). The submission unit contains documentation that is common to all countries but also documentation that is specific to individual countries and languages.

In this initial submission unit, the submission unit message identifies all the countries (as defined in an external list) and regulatory agencies as defined in an external list) included in the procedure (as defined in an external list), identifies the submitted files, and indicates the category or categories that the documentation belongs together with identification of applicable country and language (as defined in an external list). The submission unit comprises CTD sections defined by ICH (Modules 2-5) (as defined in an external list) and by EU (as defined in an external list).

This first submission unit commences the application and represents the first regulatory submission (as defined in an external list) for that application.

The submission unit also contains a number of additional items of information, including information about the product, about the applicant, the application ID (but note that this will not be assigned by the receiving agencies at this point in the process) and a submission unit description.

The initial status of the Submission review is "submitted". Note: "submitted" is not necessarily a term that would appear in the XML instance sent by the applicant.

Since this is the initial submission unit for the application, each file in this submission unit is active. The submission is then transmitted to the regulatory authorities.

Narrative Example

Technical validation of initial submission unit for Decentralised Procedure (DCP)

The Reference Member State (RMS) and each Concerned Member State (CMS) receive the first submission unit individually for Global Fixit from Acme Pharmaceuticals. Each Regulator loads the submission unit into a processing area and a technical validation of the submission unit is undertaken against a defined set of validation criteria.

The results of this validation testing can be:

  • Pass validation with no errors
  • A critical error which will prevent the submission unit from being loaded into the Review System (defined as Pass/Fail)
  • A minor error which will not prevent the submission unit from being loaded into the Review System (defined as a Best Practice check)

If no errors are identified the RMS and CMSs load the submissions into their Review Systems.

If Critical (Pass/Fail) errors are identified the RMS and/or CMSs inform Acme Pharmaceuticals (see Notification critical validation failures). The submission is not loaded into their Review Systems.

If Minor (Best Practice) issues are identified the RMS and/or CMSs may inform Acme Pharmaceuticals (see Notification of technical validation failures) and the submission unit is loaded into their Review Systems.

Once loaded into the Review Systems the RMS and CMSs undertake business validation to ensure that the content of the submission unit is appropriate for review (see Bus validate init sub unit Decentralised Proc).

Purpose

A regulatory activity under review by a regulator will undergo many exchanges between the applicant and regulator. When the regulator responds to information sent by the applicant, the content is always considered in response to an industry request. As long as the response does not include an action response, it is considered to be a Submission Content Response. For action responses, see the Regulatory Action Response storyboards below.

Diagram
Activity Diagram
Interaction List
Submission Unit sent Schema View PORP_IN000001UV
Narrative Example

The Regulator A sends a Submission Unit to industry to communicate an interim action placing an investigational study on hold, the correspondence type would be Interim Action/Clinical Hold. The Regulator A identifies the contact information for the submission (e.g., any points of contact first name and last name, Contact Type, address, phone, email, fax), product information (e.g., product type, product name, proper name, trade name, product code, product code set), regulator information (e.g., Agency, Center), submission information (e.g., regulator application number, regulator submission number, sequence (serial) number, pre-submission identifier), Submission Unit Type (e.g., category and sub category) and Comment field (free text description).

Narrative Example

Regulator A has reviewed a submission and its components and has a set of questions for the ABC Device Company regarding their product 123 and the information provided about their patient and physician labeling. The Regulator sends a list of their questions to the ABC Device as a new Submission unit within the Submission under review.

Narrative Example

Regulator A has reviewed a submission and its components and would like to clarify some questions via a meeting with Acme Foods regarding the SweetSugarCane product. Regulator A sends documentation, which includes the details of the meeting request, in a submission unit identified as correspondence.

Narrative Example

Regulator A sends Device Company ABC a letter containing questions that relate to modules 1-3 of Product Implant 123's modular premarket application (e.g., M089999) in a new submission unit.

Narrative Example

The Regulator A is sending an interim action to place the investigational study on hold. The correspondence type would be Interim Action/Clinical Hold, and identifies the contact information for the submission (e.g., any points of contact first name and last name, Contact Type, address, phone, email, fax), regulator information (i.e., Agency, Center), submission information (e.g., regulator application number, regulator submission number, sequence (serial) number, submission identifier), Submission Unit Type (e.g., category = 'Clinical Hold' and sub category = N/A) and Comment field (free text description).

On receipt of the submission unit, the regulator processes the information and is now ready for review. If there are any questions on the submission unit, the receiver uses the contact information appropriately.

Narrative Example

Regulator A sends questions about three modules submitted for Product Implant 123, including submission information (e.g., regulator submission number, (such as "Amendment" or "Supplement"), submission unit type (e.g., category = 'Information request' (such as Major Deficiency or Additional Information) and sub category = 'N/A') and Comment field (free text description).

On receipt of the submission unit in response to the questions, the response includes revised documents that apply differently to the various modules under review (i.e. Document 1 applies to Module 1, while Document 2 applies to Module 3). The Regulator processes the information and is now ready for review. If there are any questions on the submission unit, the receiver uses the contact information appropriately.

Purpose

During the regulatory review process, the applicant may send information (solicited or unsolicited) to the regulator to support their regulatory submission. Any information submitted after the initial review request is considered "additional information" to support the regulatory activity under review. The storyboards in this section illustrate the various reasons for sending information to the regulator.

Diagram
Activity Diagram
Narrative Example

The results of ongoing studies related to Global Fixit are now available; and these results show that the product is even more useful than previously thought. As a result, Acme decides to add this information to the documentation that was previously submitted in support of the Global Fixit submission. A new submission unit is created that refers to the additional documentation (i.e., the new study results) and appropriate references to relate this new information to the existing information. The submission unit is transmitted to the Regulator. The Regulator processes this submission unit.

Note: A submission unit message contains many documentation references. When a submission unit message is provided in support of a submission, individual documentation references can either be added to the submission, supersede existing documentation references in the submission, or may mark specific files as suspended from the submission.

Narrative Example

During the review of a submission, it may be necessary for the Applicant to withdraw the submission unit from further review.

Acme Pharmaceuticals executives have spent time reviewing the original Global Fixit submission unit and determined that the submission unit that was sent to support the Global Fixit submission contains a host of errors. Therefore it would be inappropriate for the Regulators to use the documentation contained within the submission unit for its review. As a result, Acme decides to withdraw the submission unit contents from consideration. A transmission is sent that indicates the submission unit contents have been withdrawn.

The Applicant sends a submission unit and suspends all submission contents for the previous submission unit.

Narrative Example

During the review of a submission, it may be necessary for the Applicant to withdraw the submission from further review or to preempt an unfavorable action by the Regulators.

Subsequent to the original submission of the Global Fixit submission, Acme scientists are able to spend time reviewing the outcome of ongoing studies of Global Fixit's efficacy. It turns out, after statistical review, that the product is not particularly effective. As a result, Acme wishes to withdraw the submission from consideration. A submission unit is created to withdraw the submission; it is transmitted to the Regulator.

Narrative Example

Acme Pharmaceuticals is sending the Regulator. A submission unit to provide the final labeling for their marketing application and identifies the contact information for the submission (e.g., any points of contact first name and last name, Contact Type, address, phone, email, fax), product information (e.g., product type, product name, proper name, trade name, product code, product code set), Regulator information (i.e., Agency, Center), submission information (e.g., regulator assigned application, regulator assigned submission number, sequence (serial) number, presubmission identifier), Submission Unit Type (e.g., category and sub category) and Comment field (free text description).

Narrative Example

The Regulator A has received a BLA amendment from BioPharm Co for a product 123 that is under review. The information provided in the submission indicates that a new supplement should have been submitted. The Regulator A sends a submission unit back to the BioPharm to indicate that the submission ID has been changed and reassigned a new submission ID and sequence number.

Narrative Example

The review process for the Global Fixit submission has extended over a substantial amount of time, and Acme has found that new information relevant to the submission has been received. For example, the original submission contained a summary of clinical pharmacology information derived from a series of studies using human biomaterial, and several new studies contain information that requires changes to this summary. Therefore, researchers working for the company have rewritten this summary and assemble and send a new submission unit with the new documentation marked as a replacement to the previous documentation.

The Regulator processes this submission unit. If the information referenced as being replaced was not provided in a previous submission unit, the current submission unit may be considered non-filed.

Narrative Example

Global Fixit has been manufactured at two locations, Big Factory and Little Factory. Acme Manufacturing now wishes to consolidate all its manufacturing at Big Factory. Therefore it is necessary to inform the Regulator of this change and to update the submission to ignore all information related to manufacturing taking place at Small Factory. Acme creates a submission unit to inform the Regulator to ignore all documentation that relates to the manufacture at Small Factory. The Regulator processes this submission unit.

Note: The documentation related to Small Factory will be suspended.

Narrative Example

The Calming Myst submission, a medication for heartburn, included a drug-substance file. However, Acme has now decided that it needs to break this file into several smaller files for better file management. In essence, the company wants the Regulator to review the drug-substance information in the more granular form. A new submission unit is created that contains multiple drug-substance files to meet the documentation requirement for drug substance information. Each file is marked as a replacement for the previously submitted drug-substance file. The original drug-substance file is now obsolete. The Regulator processes this submission unit.

Note: The life cycle related to the new more granular file is linked to the original summary file.

Narrative Example

Acme Manufacturing has prepared a submission for a product to be marketed to mountain climbers - known as High Altitude Fixit. One component of the submission will be a protocol that pertains to three different studies in the submission. It documents the protocol that was followed during those studies. When the High Altitude Fixit submission unit is prepared, it will contain, among other documentation, the protocol and other documentation providing the results of the three studies. Each of the three studies references the protocol. The submission unit transmission contains only one copy of the protocol. The Regulator processes this submission unit.

Narrative Example

Several years ago, Acme submitted a submission to market a medication for heart burn known as Calming Myst, which was to be produced under license from a European manufacturer. However, all the documentation related to the earlier submission unit has been marked as suspended because Acme was never able to come to a final arrangement with the manufacturer for the production of the product.

However, new management of the European firm is more agreeable, and Acme is confident that it will have the Calming Myst contract in hand by early next year. As a result, Acme would like to reactivate the European manufacturing for regulatory review. A submission unit message is created that refers to the previously submitted documentation and makes them active for regulatory review.

Narrative Example

Subsequent to the original Global Fixit submission, Acme researchers realize that an analytical procedure had been mistakenly categorized as a protocol of one of the studies in that previous submission's units. This was a mistake, since it should have been categorized as an analytical procedure. The company wants to inform the Regulator to change the category assignment. The submission unit that Acme transmits to the Regulator is designed to inform the Regulator that the previously referenced protocol actually should be referenced as an analytical procedure. The procedure is not re-transmitted.

Narrative Example

The original Global Fixit submission unit included a safety document. In a later submission unit for the same submission, the same safety document was mistakenly submitted again as an original file. However, new information has been received, which has led to an updated safety report. Acme wants to replace both instances of the previously submitted safety documents with the new report. A submission unit is created that contains the new safety document, and marks it as replacement for both of the previously submitted documentation.

Narrative Example

A previous submission unit for the Global Fixit submission contained a structured product labeling (SPL). Based on new data, Acme has decided to update the warning section of the label. The company wants the Regulator to review only the changes to the warning section, not the entire label. A new submission unit is created containing the changed section of the labeling file and marks it as an update to the previously submitted label. The updated SPL file section is merged with the previously submitted SPL files.

Note: As we move towards XML, sectional life cycle is possible. The life cycle of sections in the label is defined in the SPL specification.

Narrative Example

Vaccines.com would like to request a meeting with the Regulator A as they have just come into the marketplace and would like to meet with the regulators prior to submitting a marketing application. The company would like to discuss their manufacturing facilities and sends a new submission unit containing documentation, the meeting request, which includes the details of the meeting request and identified as correspondence.

Narrative Example

ABC Device Company has addressed the questions presented by Regulator A about their patient labeling and instructions for use documentation. ABC Device Company sends a response to Regulator A with the appropriate changes to existing instructions for use documentation and provides a response to the original correspondence as a new submission unit identified as an amendment to the existing submission.

Two weeks later, ABC Device Company has been able to address the questions that the Regulator A posed in regards to physician labeling. ABC Device Company sends a second response to the first correspondence from the Regulator A to add new documentation, update existing documentation and provide a response to the original correspondence. This is also sent as a new submission unit identified as an amendment.

Narrative Example

Acme Pharmaceuticals is sending Regulator A a submission unit to provide the final labeling for their marketing application and identifies the contact information for the submission (e.g., any points of contact first name and last name, Contact Type, address, phone, email, fax), submission information (e.g., regulator application, regulator submission number, sequence (serial) number, submission identifier), Submission Unit Type (e.g., category = 'label' and sub category = 'final') and Comment field (e.g., 'Submission of final labeling'). On receipt of the submission unit, the regulator processes the information and is now ready for review. If there are any questions on the submission unit, the receiver uses the contact information appropriately. On receipt of the submission unit, the sponsor company processes the information and takes appropriate action.

Submission Unit Type is a coding system used to describe the submission unit's purpose.

Narrative Example

During the assessment phase of a new pharmaceutical product, process management as well as assessors for the different areas may be involved and want to contact the sponsor directly. In a later phase, while marketing a pharmaceutical product, pharmacovigilance activities have to be performed. In any case communications, objections and responses from the specific area may be exchanged directly (for example contact not BfArM but Mrs. Miller) although the process management contact person will remain the same, e.g. Mrs. Clark within BfArM. To support this need contact persons need to also be mentioned in the submission unit with contact details and optionally their specific responsibility in relation to the product concerned and depending from the point in product life cycle the submission unit relates to.

Some regulatory authorities may also require multiple contacts for a single medical device submission. In this case each contact may play a different role. For example, the in-country application sponsor may be one contract, while a separate contact is designated for the manufacturer of the device.

Narrative Example

Acme Pharmaceuticals has decided for business reasons to withdraw their application from the review procedure.

Acme Pharmaceuticals prepares a new submission unit for Global Fixit. It identifies the type of submission unit, and that the submission unit is associated with the new submission and application. The submission unit contains a letter announcing the decision to withdraw and is sent to the RMS and CMSs where the application is withdrawn. The submission unit message identifies all the countries and regulatory agencies included in the procedure, identifies the submitted documentation, and indicates the category or categories that the documentation belongs to. The submission unit comprises dossier sections defined by EU. Additional information about the product, the applicant and submission description may also need to be provided.

The submission review status is set to "withdrawn".

Purpose

When a regulatory review results in an action or decision by a regulator, it is relayed to the applicant via a regulatory action response. The types of regulatory actions (e.g., clinical hold, pending, cleared, approvable, etc.) are specific to the regulator. The storyboards in this section illustrate the various reasons for sending a response to industry about the regulatory outcome of their submission.

Diagram
Activity Diagram
Narrative Example

Regulator A approves 5 PMA supplements after reviewing the changes to the manufacturing site and sends an approval letter to the ABC Device Company indicating the five affected PMA supplement numbers. In a week, the other 10 PMA supplements are approved after reviewing the manufacturing change submission and an approval letter is sent indicating the remaining affected 10 PMA supplement numbers, in a new submission unit identified as an action or decision.

Narrative Example

Regulator A has reviewed a submission and needs to communicate an interim or final action through a decision letter to inform Acme Pharmaceuticals about their action regarding the regulated activity (e.g., investigational or marketing applications) for Product 999. Regulator A sends the documentation, a decision letter, which includes the status of the regulated activity (e.g., approved, non-approvable, clinical hold), in a submission unit to Acme Pharmaceuticals identified as an action or decision.

Purpose

During the regulatory review process there are often scenarios when the information exchange occurs between two or more parties. These interactions may require individual exchange messages, but the messages are concurrently sent with the same or similar contents. The storyboards in this section illustrate the various reasons for sending messages to two or more parties to address the regulatory business practice.

Diagram
Activity Diagram
Narrative Example

Company A manufactures two different wrinkle fillers: one treats very deep wrinkles (Deep-Fill) and one treats superficial wrinkles (Super-Fill). Company A will submit one Modular PMA application covering the two devices.

Information Exchange #1 - December 20, 2013

Company A submits a finalized PMA Shell to the FDA (Module 0).

Information Exchange #2 - March 12, 2014

Company A submits PMA Module 1 containing 3 PDF documents: 1 document contains product manufacture information and remaining are quality management documents. Both devices, Deep-Fill and Super-Fill, are manufactured at one manufacturing site located in Wrinkle NY and the QMS Procedures and facility controls are applicable to both wrinkle filler devices.

Information Exchange #3 - September 1, 2014

FDA determines that Module 1 is incomplete and sends a deficiency letter to Company A requesting additional information. In response, Company A submits to FDA an Amendment to PMA Module 1. The submission contains the requested manufacturing information in 2 PDF document that replaces the document previously submitted and replacement for design and development information for each of the devices, Deep-Fill and Super-Fill.

Company A also submits Module 2 which contains non-clinical studies for the two wrinkle filler products.

Note: After receipt of this information, the FDA completes its review of Module 1 and closes (accepts) the module based on the information provided.

Information Exchange #4 - February 5, 2015

Company A notifies FDA that they have changed the source material for Deep-Fill to Source E. This information is submitted in a PMA Module Supplement to the previously closed (accepted) Module 1. This change contains 1 PDF for the product manufacture information this replaces the previously submitted content.

The submission contents have the following special considerations: The source material for Deep-Fill was originally covered by the Master File MAF-080012. With the change in source material, a different Master File needs to be referenced, MAF-090021. This change applies to Deep-Fill only.

The sponsor also submits an Amendment to the PMA Shell (Module 0) which describes the new manufacturing information and provides a revised timetable.

Information Exchange #5 - March 2, 2015

Company A submits the final PMA Module (Module 3) that contains all relevant clinical data and labeling information to support the full submission of the PMA. The company also submits 2 PDF document as an update in Module 2, which replaces previous Comparability Data due to the source change of their wrinkle filler, Deep-Fill.

Because this completes the Modular PMA submission, FDA considers the Modular PMA closed and assigns a new PMA number to the complete PMA Modular submission.

Narrative Example

Medical Device Submissions in multiple regions rely on inclusion of certificates as critical content to support Submission review and approval. Certificates are issued by 3rd party certification bodies, and generally demonstrate product compliance to standards or quality system compliance. The certificates are included by the sponsor as content to support review and approval of the Submission.

Certificates may be versioned for a variety of reasons and also have an expiration date. If a certificate becomes invalid, it will impact the Applications it was used to support. As a result regulatory authorities require a set of metadata to be maintained with the certificate: Certificate Number, Certificate version, Expiration Date, Model or Brand of products supported, and Certification Body ID. The submitter may have multiple certificates referenced under the same TOC heading and will need to organize the submission contents by the additional metadata.

The same certificate can be used to support multiple Submissions in different Applications. When a certificate is versioned the certificate number stays constant, but a new file will be submitted with updated meta-data. The new certificate will be replace the previous certificate (i.e., there will be CoU lifecycle with content having different combinations of keywords).The Sponsor will determine which Applications the new certificate version should be applied to.

Narrative Example

Business validation of initial submission unit for Decentralised Procedure

The RMS and CMSs have loaded the initial submission unit for Global Fixit into their Review Systems and undertake a business validation to ensure that submission content is appropriate to initiate the formal review of the submission.

The RMS identifies that Module 1 is missing Information about the Clinical Expert and prepares a request to Acme Pharmaceuticals for a replacement file to be provided (see Validation failures - common documentation).

A CMS (e.g. France) identifies that part of the information in their application form has been completed incorrectly and prepares a request to Acme Pharmaceuticals for a replacement file to be provided (see Validation failures - country specific).

Alternatively,

The RMS and CMSs have loaded the initial submission unit for Global Fixit into their Review Systems and have undertaken the business validation checks and have found no issues.

The RMS and CMSs conclude that the submission is now appropriate to initiate the procedure. The RMS informs Acme Pharmaceuticals using an RPS Message with an appropriate agency submission type and the procedure timetable. (The message will identify the information on country, regulatory agency, and type of procedure and the information product, application ID, procedure number, submission unit description).

The status for the submission review is changed to "in process".

Narrative Example

The Reference Member State (RMS) and each Concerned Member State (CMS) have each identified that the submission unit for Global Fixit from Acme Pharmaceuticals has technical issues that are of a sufficiently critical nature (Pass/Fail) as to preclude loading into the Review System.

The RMS and each CMS sends a communication to Acme Pharmaceuticals that includes the reasons identified for technical invalidation and a request that the submission is corrected and resubmitted.

Note, as the RMS/CMS have been unable to load the submission unit, the communication back to the applicant must be outside of the eCTD/RPS format.

Narrative Example

The French Regulator has identified that the application form for their country has been completed incorrectly and in order for the submission unit for Global Fixit to be accepted for review a replacement application form should be submitted.

The French Regulator sends a submission unit to Acme Pharmaceuticals which identifies the submission type, includes a document that identifies the reasons for business validation failure and requests that a replacement application form is submitted in an additional submission unit. It also identifies that this message relates to the initial submission for Global Fixit.

Narrative Example

The Reference Member State (RMS) has identified that for the submission unit for Global Fixit from Acme Pharmaceuticals to be accepted for review the missing documentation detailing information about the clinical expert should be submitted.

The RMS sends a submission unit to Acme Pharmaceuticals, indicating the submission type and includes a document that identifies the reasons for business validation failure and requests that the information about the clinical expert is submitted in an additional submission unit. (The message will identify the information on country, regulatory agency, and type of procedure and the information product, application ID, procedure number, submission unit description). It also identifies that this message relates to the initial submission for Global Fixit.

Narrative Example

Add submission unit for existing DCP for a common submission unit

Acme Pharmaceuticals has received a request from the RMS that identifies that information about the clinical expert needs to be provided and has requested that such documentation is provided.

Acme Pharmaceuticals prepares a new submission unit for Global Fixit. It identifies the type of submission unit and that the submission unit is associated with the new submission and application. The submission unit contains the new documentation which is common to all countries. The submission unit message identifies all the countries and regulatory agencies included in the procedure, identifies the submitted files, and indicates the category or categories that the documentation belongs to. The submission unit comprises dossier sections defined by EU. Additional information about the product, the applicant and submission description may also need to be provided.

Acme Pharmaceuticals sends the submission unit to all regulatory authorities in the procedure which receive it, undertake successful technical validation (Tech validate init sub unit Decentralised Procedure), and load the submission unit into the Review System. The RMS performs business validation (Bus validate init sub unit Decentralised Proc) and concludes that the common documentation is now appropriate to be able to initiate the procedure.

The RMS informs Acme Pharmaceuticals using an RPS Message with an appropriate agency submission unit type and the procedure timetable. (The message will identify the information on country, regulatory agency, and type of procedure and the information product, application ID, procedure number, submission unit description).

The submission review status is set to "in process".

Narrative Example

Add submission unit for an existing DCP with country specific documentation

Acme Pharmaceuticals has received a request from the French Regulator has identified that the application form for their country has been completed incorrectly and has requested a replacement application form.

Acme Pharmaceuticals prepares a new submission unit for Global Fixit. It identifies the type of submission unit that the submission unit is associated with the new initial marketing application procedure (identified by a procedure number). In this submission unit, the submission unit message identifies that France is the only recipient country and regulatory agency included in the procedure, identifies the submitted documentation, and indicates the category or categories that the documentation belong to together with identification of applicable country and language. The submission unit comprises categories defined by EU. Additional information about the product, the applicant and submission description may also need to be provided. It identifies that the application form for France in the initial submission unit is to be replaced by the application form in this submission unit.

Acme Pharmaceuticals sends the submission unit to the French Regulator which receives it, undertakes successful technical validation, loads the submission unit into the Review System and performs business validation and concludes that the application form is now appropriate to be able to initiate the procedure.

The France (CMS) informs Acme Pharmaceuticals using an RPS Message with an appropriate agency submission type and the procedure timetable. (If created as an RPS message then the message will identify the information on country, regulatory agency, and type of procedure and the information product, application ID, procedure number, submission unit description).

The submission review status is set to "in process".

Narrative Example

Reference Member State (RMS) preliminary assessment to Concerned Member States (CMSs) and Applicant

The Reference Member State (RMS) has assessed the content of the submission unit for Global Fixit from Acme Pharmaceuticals. The RMS creates a report of the assessment, with possible questions classified as major objection or points for clarification for the applicant. This first report is called the Preliminary Assessment Report (PrAR).

The RMS sends a submission unit to all CMSs which identifies the submission unit type. The submission unit consists of the PrAR, the product information (SmPC, PL and labelling), and the list of question (LoQ). It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by a procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

The RMS also sends a submission unit to Acme Pharmaceuticals, which identifies the submission unit type. This submission unit consists of a notification of awareness, a copy of the PrAR (but with specific confidential information excluded from the version sent to the CMS), the product information (SmPC, PL and labelling), and the list of questions (LoQ). It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by a procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

Narrative Example

The Concerned Member State (CMS) has received the submission unit from the RMS, containing the Preliminary Assessment Report (PrAR). The CMSs uploaded the submission unit in the review system and assessed the content of the PrAR.

One CMS agrees with the issues raised in the PrAR by the RMS and informs the RMS and applicant that no further questions are raised.

Another CMS reviewed the PrAR and prepares a request for supplementary information - RSI - to Acme Pharmaceuticals (classified as major objections and/or points for clarification). This request is sent to the RMS and the applicant.

A third CMS reviewed the PrAR and prepares a request for supplementary information - RSI - to Acme Pharmaceuticals. This request is sent to the RMS and applicant.

The CMS sends a submission unit to the RMS and Acme Pharmaceuticals which identifies the submission unit type. The submission unit consists of the feedback from the CMSs (i.e. additional major objections and/or points for clarification or a notification that no additional questions were raised). It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by a procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

Narrative Example

The Reference Member State (RMS) has consulted with the Applicant, Acme Pharmaceuticals, and a consensus has been reached. The discussion about the draft documentation will be carried out outside of the eCTD.

Acme Pharmaceuticals sends a submission unit to the RMS and the CMSs which contains the final English version of the Summary of Product Characteristics (SmPC), labelling and PL as well as the final applicant response document. The submission unit message identifies the submitted documentation with identification of applicable country and language for these documents. It also identifies that the submission unit is associated with the new initial marketing application procedure.

As a reaction, the RMS sends a submission unit to Acme Pharmaceuticals and the CMSs which identifies the submission unit type. The submission unit contains a letter to inform the Applicant that a consensus is reached and that the procedure is closed and the submission approved. It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by a procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

The submission review status is set to "approved".

Narrative Example

The Reference Member State (RMS) has conducted consultations with the Concerned Member State (CMS) and Acme Pharmaceuticals, the Applicant, but it was not possible to reach consensus. These discussions are carried out outside of the eCTD.

The RMS stops the clock to allow the Applicant to supplement the dossier and respond to questions.

The RMS sends a submission unit which identifies the submission unit type to Acme Pharmaceuticals. It contains a clock stop announcement and the List of Questions. It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by a procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

Within 3 months (which could be extended by a further 3 months), the Applicant sends a submission unit to the RMS and CMSs which contains the final response document. It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by a procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description. The RMS restarts the procedure following technical and business validation.

The submission review status is set to "suspended".

Narrative Example

RMS accepts dossier and adds sequence to the CMSs

In the Decentralised (DC) or Mutual Recognition (MR) Procedure the Reference Member State (RMS) is content with the applicant responses on the submission unit for Global Fixit from Acme Pharmaceuticals. The RMS informs the applicant to submit final responses to the CMSs.

The RMS sends a submission unit to Acme Pharmaceuticals which identifies the submission type. The submission unit consists of a letter. It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by a procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

Narrative Example

The RMS informs Acme Pharmaceuticals that the Responses are accepted and asks the Applicant to submit the final Responses to the CMSs. This notification to the applicant may be done outside the eCTD.

Acme Pharmaceuticals prepares a new submission unit for Global Fixit. It identifies the type of submission unit, and that the submission unit is associated with the new initial marketing authorisation procedure (identified by a procedure number). In this submission unit, the submission unit message identifies that the CMSs are the recipient countries but not the RMS, and the regulatory agencies included in the procedure.

The submission unit contains documents (final set of Responses) which are common to all countries and indicates the categories that the documentation belongs to. The submission unit comprises dossier sections defined by EU.

Other information needed for tracking purposes includes information on the product, the applicant, and submission unit description.

The CMSs regulatory authorities in the procedure receive the submission unit, undertake successful technical validation and load the submission unit into the Review System.

Narrative Example

The Reference Member State (RMS) agrees to the timetable. The RMS sends a revised timetable and a clock re-start letter/message including the date of sending the Draft Assessment Report (DAR) on Day 120.

The RMS sends a submission unit to all CMSs which identifies the submission unit type. The submission unit consists of the timetable and clock-restart letter. It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by procedure number). Other information needed for tracking purposes will include the name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

[This step is currently done outside the eCTD and may continue to be done outside the eCTD in the future.]

The RMS sends a submission unit to Acme Pharmaceuticals, which identifies the submission unit type. This submission unit consists of the timetable and clock-restart letter. It also identifies that the submission unit is associated with the initial marketing application procedure (identified by a procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

Narrative Example

The Reference Member State (RMS) has assessed the content of the submission unit for Global Fixit from Acme Pharmaceuticals including the responses to all regulators; comments received from the Concerned Member States (CMS) and consolidated these into a second report of the assessment, with a possible request for supplementary information for the applicant. This report is called the Draft Assessment Report (DAR).

The RMS sends a submission unit to all CMSs which identifies the submission unit type. The submission unit consists of the DAR and the product information (SmPC, PL and labelling). It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by a procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

The RMS also sends a submission unit to Acme Pharmaceuticals, which identifies the submission unit type. This submission unit consists of a notification of awareness, a copy of the DAR (but with specific confidential information excluded from the version sent to the CMS) and the product information (SmPC, PL and labelling). It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

Narrative Example

RMS consults the CMSs, and Applicant and reaches consensus

The CMS's final comments have been received by the RMS on day 145. There are no outstanding matters left and the RMS will close the procedure on day 150. The "End of Procedure Letter" including Product Information and possible commitments will be sent to the involved parties.

The RMS sends a submission unit to Acme Pharmaceuticals and the CMSs which identifies the submission unit type. The submission unit contains a letter to inform the Applicant that a consensus is reached, that the procedure is closed and the submission approved. The submission unit also includes a copy of the labeling documents and a list of any commitments. It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by a procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

The submission review status is set to "approved".

Narrative Example

The CMSs' final comments have been received by the RMS on day 145.

The Applicant will respond to those comments. Acme Pharmaceuticals prepares a new submission unit for Global Fixit. It identifies the type of submission unit and that the submission unit is associated with the new submission and application. The submission unit contains the new documentation which is common to all countries. The submission unit message identifies all the countries and regulatory agencies included in the procedure, identifies the submitted documentation, and indicates the category or categories that the documentation belongs to. The submission unit comprises categories defined by EU. Additional information about the product, the applicant and submission description may also need to be provided.

Acme Pharmaceuticals sends the submission unit to all regulatory authorities in the procedure which receive it, undertake successful technical validation, and load the submission unit into the Review System.

On day 180 the RMS will give its comments on the response.

Narrative Example

The Reference Member State (RMS) has assessed the content of the submission unit for Global Fixit from Acme Pharmaceuticals. It has received comments from the Concerned Member States (CMS) and consolidated these into an assessment report as detailed above. Due to divergent positions most likely a consensus will not be found and the Coordination-Group will be informed in advance.

The RMS sends a submission unit to the Coordination Group which identifies the submission unit type. The submission unit consists of the assessment report and other relevant information. It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by a procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

The RMS also sends a submission unit to Acme Pharmaceuticals, which identifies the submission unit type. This submission unit consists of the assessment report and relevant information. It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by a procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

[Currently, these steps are not carried out in the eCTD and may not be in the future.]

Supporting documents (to be provided)

Narrative Example

The breakout session has been held and the Reference Member State (RMS) provides details of the outcome to the CMSs and Applicant. Typically this might be a list of outstanding issues.

The RMS sends a submission unit to the CMSs and Applicant which identifies the submission unit type. The submission unit consists of the outcome of the breakout session and the list of outstanding issues. It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by a procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

Narrative Example

The Concerned Member States (CMSs) have received the submission unit from the RMS, containing the assessment report and the breakout group list of outstanding issues. The CMSs uploaded the submission unit in the review system and made their final review.

The CMS sends a submission unit to the RMS and Acme Pharmaceuticals which identifies the submission unit type. The submission unit consists of the final positions and key documents. It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by a procedure). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

Narrative Example

This consultation procedure is called referral and is referred to the responsibility of the Coordination Group. The RMS consults with the CMSs and the applicant. .This referral happens outside the eCTD. The regulatory status of the activity will be set to "referred to CMDh"

One optional outcome is consensus and the procedure will be finalized as outlined in section 2.2.5.18. The status of the regulatory activity review will become "approved" (see section below).

Another optional outcome could be no consensus and an extended referral procedure need to be started, but outside eCTD.

Narrative Example

Coordination Group consensus is reached and RMS sends final outcome to Applicant after referral

The Reference Member State (RMS) and each Concerned Member State (CMS) have reached a consensus on the submission unit for Global Fixit from Acme Pharmaceuticals. This decision could be an approval or a rejection.

The RMS sends a submission unit to Acme Pharmaceuticals identifies the submission unit type. The submission unit consists of the relevant documentation for the decision that has been reached. The documentation will include the letter with the decision, but could include other supporting documentation, such as the approved SPC document in the case of an approval or reasoning in case of rejection. It also identifies that the submission unit is associated with the new initial marketing application procedure (identified by a procedure number). Other information needed for tracking purposes will include name of country, regulatory agency, type of procedure, name of language, type of submission, information on the product, the applicant, and submission unit description.

The submission review status is set to "approved" or to "rejected" as appropriate.

Narrative Example

Marketing Authorisation Holder applies for a variation

Acme Pharmaceuticals is the marketing authorization holder (MAH) of several products authorized via different procedures and all containing the same pharmacologically active substance. As a centrally authorized product is involved, this will become a centralized procedure.

Acme Pharmaceuticals prepares a new submission unit applicable to Global Fixit, Wonderpil, Reachme, and Take For. It identifies the type of submission unit, and that the submission unit is associated with the new submission (regulatory activity is now variation in work share mode) and applications as mentioned. The submission unit contains an application form detailing the change and documentation all related to a new Risk Management Plan. The submission unit message identifies all the countries and regulatory agencies included in the procedure, identifies the submitted documentation, and indicates the category or categories that the documentation belongs to. The submission unit comprises dossier sections defined by EU. Additional information about the products (different product specific identifier and product names in respect to the country they are authorised for), the applicant (identical in all cases) and submission description (will apply to the submission regardless of product name differences) may also need to be provided.

The initial status of the Submission review is "submitted".

Note: The same use cases for technical and business validation apply for this regulatory activity as well.

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 Application Roles (Sorted by Artifact Code)
 Application Roles (Sorted by Display Order)
 
pointer Applicant (PORP_AR000001UV
pointer Regulatory Authority (PORP_AR000002UV
Reference

For details on the interpretation of this section, see the discussion of application roles and their relationships in the Version 3 Guide.

Description View Interactions

The organization that assumes responsibility for producing documentation for the purposes of regulatory activities such as seeking approval to either start testing or market a specified product, master file submission, etc.

Description View Interactions

The organization that reviews and maintains records on the relevant information.

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 Trigger Events (Sorted by Title)
 Trigger Events (Sorted by Display Order)
 
pointer Unsolicited Submission Unit to Regulators (PORP_TE000001UV
pointer Regulator Response (PORP_TE000002UV
pointer Solicited Submission Unit to Regulators (PORP_TE000003UV
Reference

For details on the interpretation of this section, see the discussion of trigger events in the Version 3 Guide.

Description View Interactions
Type:  User request

The user (either as Applicant or Regulator) determines they have enough information that warrants a submission unit. The user can create a new submission, amend an existing submission or withdraw a submission.

Description View Interactions
Type: 

The Regulator responds to documentation provided by the Applicant. This response might contain documents with a list of questions, an approval or hold letter, requests for meetings, or other information, including coded information representing responses documented in regulations. This response will be packaged as a Submission Unit.

It is not necessary or expected to have coordination between Submission Units submitted by an Applicant and Submission Units sent in response by a Regulator (i.e., the sequence of receipt cannot be determined by the sequence number and/or submission unit identifiers).

Description View Interactions
Type: 

Applicant responds to a Regulator's request with a Submission Unit including documents or coded information representing responses documented in regulations. This trigger also includes required scheduled reports, such as annual report.

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 Refined Message Information Models (Sorted by Title)
 Refined Message Information Models (Sorted by Display Order)
 
pointer Regulated Product Submission (PORP_RM000001UV01
Reference

For details on the interpretation of this section, see the description of RMIMs in the Version 3 Guide.

Diagram
image unavailable
Parent:  None
Description

Security, Confidentiality, and Data Integrity

Application systems sending and receiving information are responsible for meeting all legal requirements for authentication, confidentiality, and retention of the information exchanged per regional regulatory guidelines. For communications over public media, cryptographic techniques for source/recipient authentication and secure transport of encapsulated documentation may be required, and should be addressed with commercially available tools outside the scope of this standard.

Model Overview

Submission Life Cycle

The exchange of information between regulators and industry relates to multiple transactions over time that belong to one or more regulatory activities. Regulatory activities relate to one application. The submission unit, submission and application elements are described below.

Note that each region will have different regulatory processes.

RPS Submission Unit

Each exchange of information between regulators and industry is considered a regulatory transaction. Transactions are represented in the RPS model as RPS Submission Units. The entry point for the RPS message is the Submission Unit Act. Meaning, industry transmits information to regulators in the form of submission units. These submission units support the overall application.

For example, when industry determines it has enough information to support the approval of a product in that country or region, they initiate the regulatory activity by providing a Submission Unit to the appropriate regulator. In this case, the industry is the sender. Upon receipt and review of the provided information a regulator might determine that it has information in response and provides a Submission Unit back to the industry. In this case, the regulator is the sender. The industry can subsequently create a new Submission Unit which may create new Submissions, amend existing Submissions or withdraw Submissions. Submission units sent by the regulator are considered part of the Submission Act in that they can provide information relevant to the existing Submission.

fig1.jpg

Figure 1: Exchange of Submission Units between Regulator and Industry

Each Submission Unit is a single transmission of information about one or more Submissions. This relationship is defined in the message through the componentOf ActRelationship.

Each Submission Unit is categorized by its code and can be further categorized by a CategoryEvent object referenced through the componentOf ActRelationship. CategoryEvent objects may be further described using additional CategoryEvents referenced through component ActRelationships.

State of Submission Unit (i.e., status code)

Submission Units are either active (i.e., current) or suspended (i.e., no longer relevant). This concept does not have a complicated lifecycle.

fig2.jpg

Figure 2: Submission Unit State Diagram

The status codes for Submission Unit are as follows:

Status Code

Description

Active

The information is current.

Suspended

The information is considered no longer relevant.

Figure 3: Submission Unit Status Code Value Set

RPS Submission

In many instances, the result of the regulatory activity is a regulatory approval (e.g., to market a product) in that country or region. In some jurisdictions, it is possible to seek additional approvals for a regulated product through provision of additional information. In some cases additional information may be required to file about changes that do not require approval. The defined Application may have multiple regulatory review and approval processes over time.

For example, following the initial approval to market a drug product in the US or Europe, the regulatory processes allow subsequent requests for approval of the drug product (e.g., new indication) to be considered by the regulatory authorities. These are referred to as Supplements in the US and Variations in the EU - i.e., regulatory activities.

Each Submission must be associated to an Application in order to manage the overall product life cycle in that region. An Application may contain multiple Submissions, as described above, and they are connected through a componentOf ActRelationship.

The following elements provide additional information about the Submission:

Submission Group: A Submission act may also belong to a SubmissionGroup through the subject ActRelationship. The SubmissionGroup is a label used to identify several submissions as belonging to the same group.

RegulatoryReviewTime: A Submission act may also indicate a RegulatoryReviewTime through the subject ActRelationship - this element allows the sender to specify a review activity and its review time.

Review: A Submission may indicate zero or more Review acts as specified through the subject ActRelationship, which is used to indicate the existence and status of a review process, particularly in cases where multiple Regulatory Authorities may be reviewing the same product.

Regulatory Status: The Review Act may also have zero to one RegulatoryStatus through the subject ActRelationship. The regulator may provide a regulatory status for each submission. The RPS standard represents each of these approvals as Regulatory Status on the Submission within the RPS Application construct.

The Review act has a status code attribute that would be set to active on the initial submission. The formal state machine for submission objects is as follows:

fig4.jpg

Figure 4: Review State Diagram

The status codes for Review are as follows:

Status Code

Description

Active

The Review is current and open.

Aborted

The Review is no longer active as it has been withdrawn from consideration.

Figure 5: Review Status Code Value Set

Note: the actual regulatory status of a Review is represented by the code value in the regulatory status act. This code will be drawn from a controlled vocabulary to be defined and used by the regulator (see RegulatoryStatus below)

The Review Act also allows for additional information related to the Submission, and are outlined below:

Regulatory Status: The Review Act may also have zero to one RegulatoryStatus through the subject ActRelationship. The regulator may provide a regulatory status for each review completed. The RPS standard represents each of these approvals as Regulatory Status on the Review element of an RPS Submission within the RPS Application construct. Note that each regulator will define the number of Review acts for a submission based on the regulatory activity.

TerritorialAuthority: The Review act may also have zero or more Territorial Authorities defined through the Author participation, each of which may have an optional Authority (name) and Place (country).

Product Category: The Review act may also have zero or more ProductCategory acts through the subject ActRelationship.

Applicant: The Review act may also optionally identify the Applicant through the holder participation, which may belong to an Organization.

ManufacturedProduct: The Review act may also indicate the regulated products to be reviewed through the subject participation, zero or more ManufacturedProduct roles may be identified. Each ManufacturedProduct will have a Product entity that has zero or more Ingredient roles containing a Substance entity.

Mode: A Submission act may optionally have a Mode through a subject ActRelationship. The mode would be used in variation or line extension regulatory activities and must be included in every sequence of that activity; the mode codes are defined by regulatory authorities. This is not used by all regulatory authorities, but may be applicable to: a single regulatory activity (e.g. an EU Type II variation), a grouped activity (e.g. several variations grouped into a single submission or a periodic report of EU type IA variations applicable to one or more marketing authorisations), and an activity subject to a worksharing agreement (e.g. an EU Type II variation applicable to more than one marketing authorisation).

callBackContact: A ContactParty role can be specified through the participation on the Submission act. The contact information is needed so the Regulator and Submitter know who to communicate with if a problem arises. The contact could be of many types (e.g. technical, clinical, cmc) and will be based on regional controlled vocabulary. The submitter can provide either a Person (name, address, telecom) or Organization (name, address, telecom) as the Contact Party. The Contact Party may have a statusCode of either active (i.e., current) or suspended (i.e. no longer relevant). These concepts do not have more complicated lifecycle since the extra complication is not needed compared to the effort.

fig6.jpg

Figure 6: Contact Party State Diagram

The status codes for Contact Party are as follows:

Status Code

Description

Active

The information is current.

Suspended

The information is considered no longer relevant.

Figure 7: Contact Party Status Code Value Set

Certain types of submissions may be approved by one or more Regulators over time for one Applicant when the regulator only has jurisdiction over a certain territory. The approval could be for a product. Many products can be the subject of each review. It is possible that not all products in the initial review will be approved.

Bundled/Grouped Submissions: The collection of documents in a submission unit could also be applicable to more than one application. For example, a change in manufacturing can be applicable to many applications and thus need to be submitted to many applications. Accordingly, a submission unit can pertain to many submissions and each submission can pertain to more than one application. When this occurs, the grouped submission can have one tracking number (i.e. submission group.id). It is also possible that not all of the documentation in a submission unit applies to all of the applications. The submission reference relationship can be negated for each context of use. In other words, unless otherwise stated, all context of use applies to all applications referenced by that Submission Unit.

A single document may be targeted to one or more regulators or one or more submissions in the set of regulators (using the TerritorialAuthority role), or Submissions (using the SubmissionReference Act) associated with the SubmissionUnit in which the contextofUse Act is a component. If not specified, the context of use is assumed to be targeted to all regulators that receive it.

RPS Application

The exchange of information between regulators and industry is typically performed as part of a defined regulatory process specified in legislation in each country or region (e.g., 21 CFR Part 312 in the US, EudraLex Volume 1 in the EU). The RPS standard represents these regulatory processes as RPS Applications. The RPS Application provides the overall organization for the exchange of information between the parties identified by the defined regulatory processes.

Applications may be considered the electronic containers for the information submitted over time and correspond to the paper principle of a dossier for a regulated product. The Application may include the definition of Keywords (i.e. name/value pairs, e.g. species (name), rat (value)).

The RPS Application construct has several administrative objects as described below:

ReviewProcedure: The Application act may also include an optional ReviewProcedure act through the subject ActRelationship

  • For example, in a European drug product marketing applications this may take the value of the regulatory review procedure - e.g., Centralised, Decentralised, National or Mutual Recognition.

TerritorialAuthority: The Application act may also include an optional Territorial Authority role through the information participation.

  • For example, for European drug product marketing applications this is used to identify the specific governing authorities or territories to which the application is sent.

ApplicationReference: The Application act may also reference other applications through the reference ActRelationship. The referenced application is not included in the submission unit, but is used to reference previously submitted information that may support the current regulatory activity.

  • For drug product applications this could be used to relate a Drug Master File or Active Substance Master File.
  • For medical devices, Application Reference may be used to relate a product Application to a quality system application that supports it

Applicant: The Application act may identify one or more Applicants related through the Holder participation

  • For example, this identifies the organization sending the RPS Application to the Regulator, which may be the Applicant (e.g., Applicant or Sponsor) or another party that sends on behalf of the Submitter (e.g., Agent for the Submitter, CRO).

Keyword Definition: The Application act may include one or more Keyword Definitions through the referencedBy ActRelationship

  • For example, the keyword definition may have a type of "manufacturer" and a value of "BigFactory". The keyword definition would enable the submitter to set one or more values for the accepted keyword types.

The Keyword definitions may have the following states:

fig8.jpg

Figure 8: Keyword Definition State Diagram

The status codes for Keyword Definition are as follows:

Status Code

Description

Active

This keyword definition is active, and is available. All keyword definitions start in an active state.

Suspended

This keyword definition is no longer relevant. It is no longer available for use.

Figure 9: Keyword Definition Status Code Value Set

Submission Content

The submission unit will include the contents of the regulatory submission by describing the documents and placement of the document within a table of contents. Additional meta-data can be provided on the document and/or context of use.

ContextOfUse

ContextOfUse (CoU) codes are controlled vocabularies used to define the use of a document in the Submission Unit, and ultimately, its placement in the overall table of contents for the regulated product type as defined by a country or region. A Context of Use is a reference to a document in a particular submission unit with a particular code value that assigns the document to a specific section of the table of contents, further classified by references to Keywords. A single document may be assigned to more than one section of the table of contents, i.e., be associated with more than one ContextOfUse (see Document Reuse).

ContextOfUse codes are typically provided as controlled vocabulary lists by the regulatory authorities in each region for each regulated product class. In some regulated industries (e.g., drug products) the controlled vocabulary (i.e., the CoU codes) can be harmonized across regions.

A single Submission Unit may include codes from multiple lists or even multiple authorities, as permitted by the particular submission type. For example, a US FDA New Drug Application (NDA) may include CoU codes provided by the International Conference on Harmonisation (ICH) eCTD code list, and by the US FDA Center for Drug Review and Evaluation list, and particular codes specific to NDA applications may not be used for other application types.

A Context of Use may be limited to particular regulators by specifying one or more TerritorialAuthority roles through the primaryInformationRecipient Participation. It can also be restricted to being relevant to only particular Submissions through the use of the SubmissionReference act, through the subjectOf ActRelationship.

Context of Use States (i.e., status Code)

The following state diagram indicates the states that are relevant to the context of use element.

fig10.jpg

Figure 10: Context of Use State Diagram

Context of Use only assume a subset of the provided states. When a document is referenced to the regulatory authorities in a specific CoU, its status becomes "active." Context of Use that are "active" are rendered "obsolete" when they are replaced , and this should be done explicitly using the replacement relationship between the new version of the Context of Use and its predecessor (i.e., Related Context of Use).

A Context of Use can be rendered "suspended" by a status change to an existing Context of Use. RPS will NOT provide a mechanism for a submitter to physically delete submitted content. If a Context of Use is rendered "suspended," that Context of use may become active again. Obsolete and suspended context of use elements cannot be replaced. If a Context of Use is rendered "obsolete", that context of use cannot be made active again. Instead, a new Context of Use should be instantiated to "replace" the current Context of Use. The new Context of Use will point to appropriate document. A Context of Use can be suspended by the submitter sending a copy of the same document object (i.e., with the same id) and a status code of "suspended.

The status codes for Context of Use are as follows:

Status Code

Description

Active

This Context of Use is active, and is available. All documents start with an active state. Active also means the document is current.

Obsolete

This Context of Use was superseded by a replacement and is now obsolete. It is no longer available.

Suspended

This Context of Use is no longer relevant, and is no longer available.

Figure 11: Context of Use Status Code Value Set

As described above, a context of use has a reference to a specific document in a particular submission unit with a particular code value. Because a document may have several contexts of use, it is possible that each context of use will have different statuses and still reference the same document.

For example, a document D0 relating to manufacturing processes might be filed under two different manufacturers Q and R (i.e., D0 would be associated with two different CoU objects, CQ and CR). If the manufacturing process changed at R but not at Q, the document D0 would NOT be replaced, rather a new document, DR, would be created. DR would be submitted along with an updated CoU CR. Document D0 would remain active, as would CoU CQ. It is expected that RPS management tools will provide their users with a 'used in' list showing the associated contexts of use for any document object.

Context of Use Keywords

To enable further distinction between multiple documents using the same CoU code, the Keyword act may be provided on individual ContextOfUse acts to provide further differentiation. The Keyword act contains a Code from either a KeywordDefinition Act (connected to the Application act through the ReferencedBy ActRelationship), or a coded value from a controlled vocabulary list.

Keywords have a code, which indicates a value, e.g. an identifier which means "oral" and a codeSystem which indicates the type of keyword, e.g. an identifier which means "route of administration".. Some keywords will be in predefined code lists, which contain their values as both text and code, but the keyword name will be determined or inferred from the code system id or name. User-defined keywords can be defined in an application by a keyword definition and have their value given in the value attribute of the definition object, and their descriptive name assigned in the displayName attribute of the definition object.

The combination of contextofUse Codes and Keywords enables submission assembly and review tools to create a logical organization and grouping of the submitted content to be presented to the end user independent of the sequence the information is provided within the submission unit.

  • For example, user-defined Keywords would be used in CTD section 3.2.S to provide further specificity regarding the drug substance and manufacturer. The KeywordDefinition would be used to provide specific, user-defined text to further distinguish a set of documents referenced with the same Context of Use code

Please note that the RPS message does not include the ordering information of the keywords within a specific table of contents heading -- this is determined by the Regulator as a separate process.

Priority Number

The order by which documents are organized in a dossier section is important in order to communicate the importance/priority of a document relative to the other documents in that section. The use of priority numbers allows the sender to provide a logical order for review of the documents, and to maintain a logical order of the documents during life cycle changes.

For example, multiple study documents can be submitted to support a specific clinical indication. The applicant needs the ability to specify which of the study documents should be reviewed in a particular order - i.e., priority numbers organize content appropriately within a section of the table of contents.

The Context of Use priority number is related to the order of the context of use elements within a submission unit that may be used for the presentation of content under a specific heading and keyword combination. The life cycle of content will also need to address the following changes to content over time:

  • The addition (additions or insertions) of new Context of Use elements, over time, requires the same controls in order to ensure the relative priority of the content is maintained with respect to the existing submission content in the current view of that section of the application.
  • The removal of new Context of Use elements, over time, requires the same controls in order to ensure the relative priority of the content is maintained with respect to the existing submission content in the current view of that section of the application.
  • The reordering of existing Context of Use elements, over time, requires the same controls in order to ensure the relative priority of the content is maintained with respect to the existing submission content in the current view of that section of the application.

Therefore the use of priority number within Context of Use elements with the same code value and their keyword combinations will enable the receiver to order submission contents over time.

Document

The content of an electronic regulatory submission is provided in named digital files of various formats (e.g., .pdf, .xml, .jpg) as may be required by the regulator. These files are not embedded in the RPS XML message but are usually transmitted in conjunction with the RPS message and are represented as document elements in the message.

A document comprises (i.e., references) exactly one file and the reference to the file is the path/name of the file carried in the document.text attribute.

Document #1

Document #2

id: dd1234

title: A Document

text: path0/path1/name1.pdf

statusCode: active

id: dd5678

title: A Second Document

text: path0/path1/name2.pdf

statusCode: active

Figure 12: Example of document elements and their attributes

Stated more formally, the unit of content managed and referenced in RPS is the document, represented in the model by the class document (of type document, a subtype of class act). The attributes of document are:

  • id : a required unique identifier
  • title : an optional text string
  • text : an optional attribute used to reference a file in a simple document

Document Keywords

To enable further distinction between multiple documents using the same CoU code where the classifications are fixed for all uses of the document, the Keyword act may be provided on individual Document acts to provide further differentiation. The Keyword act contains a Code from either a KeywordDefinition Act (connected to the Application act through the ReferencedBy ActRelationship), or a coded value from a controlled vocabulary list.

These keywords behave exactly as those referenced in Context Of Use elements, with the exception that because there is no life cycle and status on a document, a keyword on a document may not be changed. Instead, if keywords must be changed (for instance due to error), the file must be referenced as a new document element with new keyword values.

Grouping of Documents

When more than one document needs to be defined for a group or collection under the same context of use code, keywords will be used to further group documents. For example, a protocol for a study might be provided as a single PDF (protocol.pdf). This PDF is presented as a document element in the RPS message and is assigned the appropriate keyword for "protocol-or-amendment" to further describe the documentation relative to the other documentation being submitted related to Study XXX. The use of a document within a Submission Unit requires assignment of new unique numbers for contextofUse.id.

Document

Context of Use

id: vc239

title: Protocol for Study XXX

text: Path0/path1/protocol.pdf

component.priorityNumber =1

id: 23er45

code: code="5.3.5.1" codeSystem="OID"

statusCode: active

derivedFrom

documentReference@id: vc239

referenceBy

keyword : code="protocol-and-amendments" codeSystem="OID"

keyword : code="Study XXX" codeSystem="OID"

Figure 13: Associating a document to a specific Table of Contents heading (i.e., context of use)

Note: the priority value assigned to the CoU as a component of the submission unit is not part of the CoU object itself, but specifies the relative display position of the particular CoU with respect to other CoUs that carry the same code value and keywords. Since this priority value is a real number it is always possible to insert a CoU between any two previously submitted CoUs (e.g., priority 1.5 can be submitted to specify the display between priorities 1 and 2.)

Document Reuse

Since the same information might need to be submitted to different sections of the same application or to support multiple applications, it is imperative that the standard allow for the re-use of documents. Reuse is accomplished by using the ID scheme (through the ID property of the II datatype) in the DocumentReference Act of contextofUse. The ID scheme allows a context of use in one application to provide a reference to a document that was submitted in another submission or even another application.

The contextofUse Act provides the relationship of a document to a section of the Submission Unit (or Application). Since a submission unit can contain multiple contextofUse acts, this class can be used to indicate each assignment of a document to a section. Looking across multiple submission units, it is possible to identify a single document's context in multiple applications as needed.

For example, a document is submitted to support each of the two manufacturers for the drug substance in an application. The submission unit would specify the use of the document under the respective context of use code and keyword combination.

Note that one Context Of Use instance associates exactly one Document with exactly one heading in the Table Of Contents, as specified by the code. Where multiple Documents under the same heading, that is, where several Context Of Use instances (each referencing a single document) specify the same code value, then the CoU priority, the associated Keywords and the Context of Use code together determine the position of those Documents in the submission, but each Document still appears only once in the sequence.

Document

id: dd1234

title: A Document

text: path0/path1/name1.pdf

Figure 14: Document element

Two contexts of use for the document would then be created, both referencing the same document id (i.e., dd1234).

Context of Use #1

Context of Use #2

component.priorityNumber =1

id: ff43e

code: code="3.2.s.1.1" codeSystem="OID"

statusCode: active

derivedFrom

documentReference@id: dd1234

referenceBy

keyword: code="BigFactory" codeSystem="OID"

keyword: code="Substance-1" codeSystem="OID"

component.priorityNumber =1

id: qw0987

code: code="3.2.s.1.1" codeSystem="OID"

statusCode: active

derivedFrom

documentReference@id: dd1234

referenceBy

keyword: code="LittleFactory" codeSystem="OID"

keyword: code="Substance-1" codeSystem="OID"

Figure 15: One Document referenced by two Context Of Use elements (i.e., document reuse)

A reference to this same document could similarly be established from another application entirely as long as the document id is accessible on the receiving end of the message. Regional implementation guides will specify the extent of document reuse allowed by the local regulatory authorities.

Context of Use Life Cycle

When existing documentation is modified in a subsequent SubmissionUnit, there are two operations that should happen:

1) A new Document must be created within the Application Act; this indicates that new content is available.

2) A new version of the contextofUse that was derived from the previous version is created within the SubmissionUnit act and the replacementOf ActRelationship that points to the previous contextofUse (relatedContextOfUse). This indicates that the new content is being used in the particular Contexts of Use for the replaced document.

For example, in a previous example a document (id=dd1234) was presented as being used to support two manufacturers in the drug substance section of an application. In order to revise that document the two steps above must be performed.

New Document (Submission Unit #1)

Context of Use #1 (Submission Unit #1)

id: dd1234

title: A Document

text: path0/path1/name1.pdf

component.priorityNumber =1

id: ff43e

code: code="3.2.s.1.1" codeSystem="OID"

statusCode: active

derivedFrom

documentReference@id=dd1234

referencedBy

keyword: code="BigFactory" codeSystem="OID"

keyword: code="Substance-1" codeSystem="OID"

Figure 16: Submission Contents in SubmissionUnit #1

New Document (Submission Unit #2)

Context of Use #2 - Replacement for CoU#1 (Submission Unit #2)

id: dd5678

title: A Document

text: path0/path1/name1.pdf

component.priorityNumber =1

id: dd67a

code: code="3.2.s.1.1" codeSystem="OID"

statusCode: active

replacementOf

relatedContextOfUse@id=ff43e

derivedFrom

documentReference@id: dd5678

referencedBy

keyword: code="BigFactory" codeSystem="OID"

keyword: code="Substance-1" codeSystem="OID"

Figure 17: Submission Contents in SubmissionUnit #2 (Replacement of Content)

Suspending Context of Use

There is occasionally the need to suspend (e.g. remove or withdraw) a Context of Use, which have previously been submitted (e.g., erroneously submitted or no longer relevant to the review of the application). To do this, a subsequent submission message will specify the Context of Use id to be removed and indicate the status as being suspended. For example, in order to remove a Context of Use and its referenced document from one of its locations in the application a subsequent submission unit would contain the following Context of Use element.

Context of Use #2 - Suspend Context of Use Submission Unit #3)

component.priorityNumber =1

id: ff43f updateCode="NC"

code: code="3.2.s.1.1" codeSystem="OID" updateCode="NC"

statusCode: suspended updateCode="R"

Figure 18: Suspend a Context of Use

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 Hierarchical Message Descriptions (Sorted by Title)
 Hierarchical Message Descriptions (Sorted by Display Order)
 
pointer Regulated Product Submission (PORP_HD000001UV01
Reference

For details on the interpretation of this section, see the description of HMDs in the Version 3 Guide.

Description

This is the HMD for the Regulated Product Submission, submission units message.

Base Hierarchical Message Description Goto RMIM Table View Excel View

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 Interactions (Sorted by Title)
 Interactions (Sorted by Display Order)
 
pointer Submission Unit sent (PORP_IN000001UV
Reference

For details on the interpretation of this section, see the definition of Interactions in the Version 3 Guide.

Description Schema View

The submission unit is sent from any role to any other role in the regulatory submission process

Trigger Event Unsolicited Submission Unit to Regulators PORP_TE000001UV
Transmission Wrapper Send Message Payload MCCI_MT000100UV01
Control Act Wrapper Trigger Event Control Act MCAI_MT700201UV01
Message Type Regulated Product Submission MT PORP_MT000001UV01
Sending and Receiving Roles
Sender Applicant PORP_AR000001UV
Sender Regulatory Authority PORP_AR000002UV
Receiver Applicant PORP_AR000001UV
Receiver Regulatory Authority PORP_AR000002UV

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