Regulated Product Submission Release 2 (RPS R2) Business Scenario Development

Regulated Product Submissions | RPS R2 Project | RPS R2 Business Scenarios

PARTICIPANT INSTRUCTIONS

Please use this page to develop content for the Regulated Product Submission business scenarios. To edit any individual scenario, click on the edit hyperlink for the section. If you wish to discuss any scenario, go to the discussion tab for this page click on the edit hyperlink for the section corresponding to the scenario or general discussion topic. When you have finished your editing, click on the Save page button.

Introduction

In its primary form, this page consolidates the information drafted and discussed during the business scenario development sessions at the July 24, 2008, Requirements Kick-off meeting in Silver Spring, Maryland. The business scenarios have three categories, corresponsing to the three scoping statements:

• Two-way Communication
• Referencing
• Information about the Submission

Scenarios

Two-way Communication

Submission Activities

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	Request for [[Submission (RPS)|Submission] Number (with the idea that this may be done in an automated pre-submission manner).
Additional Information	Review Guidance Documents from each Authority (Note: May be difficult for EU)
Issues and Questions	Should Post-market Commitment be included in Regulatory Actions? What are the definitions of Correspondence and Message? What differentiates a Submission Unit from correspondence? Will any correspondence get part of the application? It is usually considered part of the Application documentation. Can this business scenario also capture the administrative activities (i.e., technical issues, validations, etc.)?

Meeting Requests and Responses

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	Request Meeting (e.g., End of Phase I Meeting, Phase II Meeting, Meeting during review, Pre-Submission Meeting) Meeting request may come from either regulated industry or regulatory authority Meeting request response (from requested party) Related pre-meeting materials should be sent from one party to another Resulting meeting minutes, materials, action items should be sent
Additional Information	-
Issues and Questions	Are there specific metadata requirements? Will the activities (request meeting etc.) fall into the scope of correspondence? Would it be valuable to categorize minutes as a submission unit because it might be relevant for future regulator decisions or it may define some aspects of the upcoming study?

Follow-up/Post-market

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	Regulatory Authority asks Regulated Industry about technical issues based on field experience Currently this occurs via e-mail, fax or phone correspondence
Additional Information	-
Issues and Questions	Does this only occur on a postmarket basis due to some field activity? Is this based on a field inspection (compliance) that may result in questions to the regulated industry based on information that was not required to be submitted to the regulatory authority?

Pre-submission Activities

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	Communications between regulators to plan details of review Communications between sponsor and regulators May take the form of one of the following: – Face-to-face meetings – E-mail – Phone – FDA Meeting Minutes Meetings for a contractor to discuss facility requirements (sponsor requested meeting) Giving overall advice on planned submission or development activities Giving “scientific advice” (relates to one or multiple applications) Communications may not ever connect to a submission
Additional Information	-
Issues and Questions	The group indicated that "pre-submission" requires definition.

Informal Interactions

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	Questions not associated with a submission Questions associated with a submission
Additional Information	Refer to FDA/CDRH Guidance for Interactive Review
Issues and Questions	How are these conversations recorded today? Are all communications captured in a letter or e-mail? Do they all become part of the official record? To formalize the documentation of phone calls may be very time consuming and therefore realistically not performed. E-mail communication in a highly structured form will require, for example, a portal providing all the relevant metadata. Again, it will not be feasible to rekey all metadata again and again manually even if you use the reply function. Maybe a request or an option should be foreseen. If this becomes automated - How does the “system” weed out the “out of office” type of e-mails? This scenario needs examples of questions that may be considered “informal”

Waiver Requests

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	Sponsor sends Waiver Request related to a submission Sponsor sends Waiver Request not related to a submission
Additional Information	-
Issues and Questions	This scenario needs examples of waivers

Notification of Decision

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	Regulator(s) notify sponsor(s) and/or other Agencies of decision regarding the submission (and/or reviewable unit) Example of a multilayered – combination product (includes indication, formulation, clinical trial, manufacturing change, raw materials) Conditions/Status Options – Yes with No Conditions – Yes with Conditions that are open ended (fixed duration) – Yes with Conditions that are open ended (lifecycle commitment) – Yes with Conditions that are closed – No with Justification – No (conditional) – Reimbursement
Additional Information	-
Issues and Questions	Are there any other status options?

Recalls

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	Health Authority contacts sponsor of required recall
Additional Information	Example: FDA/CFSAN > Court > FDA > Sponsor Example: Health Authority > Multiple Sponsors for a mass recall for products for excipients
Issues and Questions	-

Withdraw from Market after Approval

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	The Regulatory Authority contacts sponsor and/or other regulatory authorities requesting withdraw from market for application/product(s) The Sponsor contacts the regulatory authority of withdraw from market for application/product(s)
Additional Information	More common for the sponsor to withdraw application If a Master File has been reference once, the application cannot be withdrawn.
Issues and Questions	-

Public Health Risk Notification

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	The Regulatory Authority may contact other Regulatory Authority regarding regulatory actions for public health risk
Additional Information	Within a BoH BoH to BoH (is this out of scope?) BoH to notify Sponsor
Issues and Questions	DEFINE ACRONYM: Does BoH mean Board of Health?

Labeling Negotiations: Request for Additional Information

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	Once the sponsor submits labeling the Regulatory Authority may request/suggest changes Negotiations may be conducted by e-mail or phone
Additional Information	-
Issues and Questions	What is captured by the Regulatory Authority about the negotiations? Are questions asked? – Is there a change to the documentation that results from the questions asked? – Is there a mechanism to ask follow up questions and/or clarification to the Regulatory Authority’s questions/suggestions/change requests?

Interagency Negotiations

Actors	Regulatory Authorities
Description	One Agency (Agency Division) asks another Agency a question or shares comments; the receiving Agency can send answers Informal assessment process (at some agencies); when it impacts the decision it is formal) Formal communication is traced as condition/commitments. Optional question or answer can refer to documentation, application or submission.
Additional Information	-
Issues and Questions	Can the two agencies exchange questions once the negotiation is initiated?

Questions about where to find content (“I can’t find it”)

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	Information was included in the submission unit, but the reviewer is not able to find the information Sponsor responds (e.g., identification of the location with previously submitted documents, I have it and will send it, don’t have it and will create it)
Additional Information	This communication is accepted by e-mail, phone, fax, or formal letter.
Issues and Questions	Is this an informal interaction? Once the information was not located within previously submitted documentation, is that when it becomes formal?

Questions from Sponsor to Agency and Resulting Response

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	The sponsor contacts the Regulatory Authority regarding questions on an application. For example, mid-study the sponsor needs advice from the Regulatory Authority on the study. – Feedback on study (data sets from safety signaling) – Whether to continue with the study – To ask if additional (3rd year) data is needed The questions can be to clarify content, placement, technical, standards The Regulatory Authority will provide a response
Additional Information	This communication is accepted by e-mail, phone, or formal letter
Issues and Questions	-

Questions from Regulatory Authority and Sponsor Response

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	Agency creates questions to send the sponsor Sponsor receives a number (multiple) of questions Questions may or may not have timelines (due dates) Sponsor may respond to one or many or all of the questions at once or at different times Agency needs to track when all of th questions have been answered Some negotiations may happen (i.e., when there are questions about questions that require clarification) Clarifications can be received by e-mail or phone Agency may approve the response to question 1 but need additional information after receiving the response to question 2 The status will remain open for all responses that the Agency finds inadequate Multiple responses may come in for one question over time. For example, the response may require input from the applicant (some amendments or clarifications), from an active substance master file holder (amendments on the closed parts) and a Member State (composition of the referenced product). The applicant may need to send the response to multiple Member States.
Additional Information	-
Issues and Questions	-

Identify Administrative Actions

Actors	Regulatory Authority
Description	The Regulatory Authority identifies that the submission unit is incorrectly submitted (e.g., a technical issue or incorrect classification of material) Example, a submission is received as an amendment, but it the submission meets the criteria for a supplement. The regulatory authority will make a change in the classification and inform the sponsor of the change.
Additional Information	-
Issues and Questions	Are there any other examples?

Referencing

Reference Document within Submission Unit

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”)
Description	A reference from a location (document, TOC) to another piece of information within the same submission unit For example, reference a clinical study from a clinical summary
Additional Information	“Reference” is one of the following: Non-retrievable, information only reference Retrievable (electronically, on demand), maintenance required
Issues and Questions	-

Referencing Document between Submissions

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”)
Description	Referencing to/from documents within a submission (original to amendment) Examples include referencing the CMC information from an original submission in an amendment where the sponsor is responding to a deficiency regarding this information
Additional Information	Link this to Request for Additional Information – Questions from Regulatory Authority and Response from Sponsor
Issues and Questions	-

Referencing outside Submission Unit, but within Application

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”)
Description	Link from a source object (document, TOC) to a target object in a different submission unit, but within the same application Example: Link from a summary document in a sNDA to a CMC document submitted in an original NDA for the same compound.
Additional Information	-
Issues and Questions	How is this different than what is covered under RPS R1?

Reference Information in Another Application

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”)
Description	Provides the ability to reference information from a separate application that is owned by the sponsor. Example is referencing an IND from a NDA This allow referencing from a component of Application A to another Component in Application B.
Additional Information	The context which the documentation is being used in each application may need to be specified. The Sponsor may want to use the same content across applications, but in a different context in each.
Issues and Questions	Need an example of this scenario. Would it be a reference to study data that was provided in a previous submission (IND) that has not changed and should be referenced in a subsequent submission (NDA)? How is this different from what is covered under RPS R1?

Referencing Information Owned by an External Party

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Master File Holder
Description	Sponsor wants to refer to information outside of their own application, which is owned by an external party. Sponsor A would get permission from Sponsor B (Holder of Reference Master File)
Additional Information	-
Issues and Questions	Is the Right of Reference Request for this scenario required? What if a letter of authorization is withdrawn?

Updating Information that Links to Other Information

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities Master File Holder
Description	Best Pharma has submitted an application with document that has reference to other documents within the application and to different application(s). This submission has been received by the Agency and they have validated the references. Subsequent to the original submission, Best Pharma has new CMC information that needs to be updated. A maintenance submission is submitted with an updated document, which has updated reference from what was submitted in the original submission.
Additional Information	-
Issues and Questions	-

Update a Referenced Document in a Previous Submission

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”) Regulatory Authorities
Description	The Table of contents of Submission A references two documents A21 and A54. Document A21 references document A54. In subsequent Submission B, its table of contents references a document in its submission, Document A6, which should replace the document A54 in Submission A. It does this by referencing Document A54 in Submission A and indicating Document A6 should replace it. Reference in Document A21 needs to be changed to reference Document B6. Example, Investigator brochure submitted last year needs to be updated with a newly submitted IB. The IB is referenced by the protocol.
Additional Information	-
Issues and Questions	-

Indirect Referencing

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”)
Description	Reference information source that in turn references a secondary source. Example, sNDA (new indication) references an original NDA, which in turn references an IND
Additional Information	-
Issues and Questions	-

Reference Paper Information from Electronic Source

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”)
Description	An electronic source submission references information that does not exist in any electronic reference“able” format. The referenced information only exists in paper. Example: New indication sNDA reference older paper NDA for non-clinical safety information.
Additional Information	-
Issues and Questions	Should this information be provided electronically? Even if it exist in paper at the Regulatory Authority? How would that reference be made? By submission number? TOC item? Volume number? Can this be standardized? How can one ensure that the documentation will persist from a records retention perspective if it is not available electronically with the new record? The Original and sNDA may be on a different retention schedule if a long period of time has elapsed.

Reference External Electronic Source/Non-Retrievable

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”)
Description	This allows the sponsor to include a link outside or external to the application, but the information not displayed within the current review tool. This could require the requestor to access another system to review the data or content in relation to the external link.
Additional Information	In case of pharmacovigilance activities, it might be useful to have links available between multiple PSURs from different companies regarding the same active substance. In case of work, sharing one submission may be related to several marketed products.
Issues and Questions	This needs an example. What type of information are we referencing? Is it an external repository? Is this for the example of annotated ECG?

Reference Electronic Source/Retrievable

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”)
Description	Generic Pharma submits and ANDA to a Regulatory Agency. As part of the submission, Generic Pharma needs to reference the original inventor labeling information posted on the Agency’s website. Generic Pharma references the original labeling information by establishing a retrievable link to the Agency’s website.
Additional Information	-
Issues and Questions	What if the website is updated after the submission and reference to the information? How do you handle references that have been changed after the submission reference? Nested references may lead to outdated or replaced information.

Referencing Approval Information

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”)
Description	Information is submitted in a modular format and receives approvable status. Several modules and letters are exchanged. The final application would consist of links to the series of approvable letters.
Additional Information	-
Issues and Questions	Could this also include references to approvals external to the applicant to note previously approved products that are similar (i.e., substantially equivalent).

Provide Access/Permission to a Submission

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”)
Description	Investigator IND Information requires the investigator to issue an allowance to do their own IND so they can conduct their study, but this information must be referenced during annual reports or safety reporting. To access submitted information (Investigator IND information), the sponsor asks for permission of the investigator to access the IND and inform the Agency of the Access/Permission
Additional Information	Permission should include: Sponsor ID, investigator ID, access to what (and where is it, what agency, center), access level (granularity of reference or permission to what is in the file), date permission was given and/or withdrawn.
Issues and Questions	Does this apply outside the U.S.?

Permit Use of Master File/Master Access

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”)
Description	DMF or Master File (global). For instance, manufacturing may be proprietary to, manufacturing company. For Devices, would be “indicator” Drug/Device patterns - maybe you have a product and use different inhalers or different devices, and you don't have the device information, you don't need to build the inhaler, you just need to put your product in it Genetics/Innovator- there is not a physical connection between the generic application and the innovator, but there would be some kind of a connection. No "permission" Request Permission Permission Given
Additional Information	Permission including the following information: sponsor ID, DMF ID, access to what (and where it is, what agency, what center), access level (granularity of reference OR permissions to what in the file), date permission given or withdrawn Letter of authorization form DMF holder – can a LOA be used for multiple products if the DMF holder has not given explicit reference to an application only to the Applicant? How is that reference to be used?
Issues and Questions	For EU, how much referring do they do between EMEA and others...? Also, for the EU, is it an open vs. closed DMF? This would affect access level.

Comparison Information

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”)
Description	Comparator information - head-to-head drug information - is usually investigational, when you are comparing yourself to another drug. You would have to gel the other product, or reference it if it is not already on the market One company requests Permission Another company gives Permission
Additional Information	Permission including the following information: sponsor ID, product ID, access to what (and where it is, what agency, what center), access level (granularity of reference OR permissions to what in the file), date permission given or withdrawn Note: if it is an approved drug, you would just go and buy it off the shelf, would not need to gel permission. Related to predicate products (e.g., 510K submission)
Issues and Questions	-

Information about the Submission

Information about the Submission

Actors	Regulated Industry (e.g., Sponsor, Applicant, “Submitting Entity”)
Description	This refers to providing basic administrative information about the message including, but not limited to: Unique identifier (associates all submissions for a specific application) Application information (includes Product type) Submission information Sponsor information Submitter information Country Language Application/submission number (already in RPS1)
Additional Information	Forms are changed and/or duplicate data is provided in forms Remove data redundancy in information processing Need to have the ability to remove a product from a submission in the case of devices. Assess the common forms across the regulatory authorities.
Issues and Questions	How is the change in identifying information during the submission lifecycle processed? Does this topic include the request or option to provide available meta data from the Authority when completing forms via portal or in some different technical solution? There are intentions of European Agencies to provide online accessible data to populate forms, which might be uploaded directly or downloaded and be added to the submission burned on DVD/CD. Will that be supported by RPS R2. How do you handle changes to applicant (ownership) in the middle of a submission review? Changes to product names? …etc.