Learn how to enable combination product Case processing and Submissions.
About Combination Products
Vault Safety supports end-to-end Case processing for postmarketing Combination Products, including those with device constituents. This capability includes Submission rules that adhere to the FDA’s postmarketing safety reporting (PMSR) requirements for combination products. Combination Products contain multiple constituents and any combination of drug, device, and biologic components. You can create combination products by applying the Combination Product object type to a Product.
Admins can set up and manage combination products using the Combination Product object type within the Product object. A Combination Product can contain multiple Product Constituents and Combination Product Registrations. Product Registrations are a key part of setting up Combination Products, as Vault relies on these registrations to generate the appropriate Submission records for each constituent part. A Product Constituent is a single drug, device, or biologic component within a combination product. These are also known as “constituent parts.” In Vault Safety, these are managed using the Product Constituent object.
Using these records, when processing Cases concerning that Combination Product Vault downloads and generates Case Assessments for each product constituent. Once the Case is Approved, Vault Safety generates the required Transmissions, determined by the Product Registrations and your Vault’s reporting rules.
Prerequisites
Your Admin must configure the Combination Product object type and Product Constituent and Combination Product Registration objects. Enable Combination Products provides instructions.
Add a Combination Product
- Go to Business Admin > Objects > Products.
- On the Products page, select Create.
- In the Create Product window, select Combination Product, and then select Continue.
- On the Create Combination Product page, complete the following fields:
- Organization (
organization__v): Select the Organization to which the product belongs. When adding a Case Product, the Case must be associated with this organization to allow users to select this product. - Product Name (
name__v): Enter the primary name of the product. Vault Safety references the product using the name that you enter in this field. When a Case Product references this Product record, Vault uses this field to generate the Case Product Name. - Combination Type (
combination_type__v): Select one of the following options to describe the combination type:- Single Entity: Multiple components that are combined and produced into a single entity.
- Co-Packaged: Multiple separate products that are packaged together into a single product.
- Cross-Labelled: Multiple products that are packaged separately but are intended for use together.
- Abbreviation (
abbreviation__v): Enter the abbreviated name for the product. This field is for reference only - Generic Name (
generic_name__v): Enter the generic name for the product. For Device-type products, this field is used in report generation for FDA E2B(R2), FDA VAERS E2B(R3), and FDA MedWatch 3500A report formats. - Manufacturer (
manufacturer__v): Select the organization that manufactures the product, if it is different from the one selected in the Organization field. For Device-type products, this field is used in report generation for FDA E2B(R2), FDA VAERS E2B(R3), and FDA MedWatch 3500A report formats. - Core Datasheet (
datasheet__v): Select the Core Datasheet for the product family. Datasheets are used to automatically detect expectedness for an adverse event and the suspect or interacting Case Products.
- Organization (
- Select Save.
Next Steps
Add Product Constituents and Product Registrations.
Combination Product Constituents
Product constituents are the individual components that make up a combination product. When you add a Combination Product record to your Vault, ensure to add the Product Constituents.
Note: Product Constituents reference Product records. Before you can add a Product Constituent, you must first set up the Products.
Add a Product Constituent
- Go to the Combination Product record to which you want to add the Product Constituent.
- Expand Product Constituents.
- Select Create.
- On the Create Product Constituent page, complete the following fields:
- Combination Product (
combination_product__v): The parent Combination Product for which this product is a constituent part. Vault Safety automatically populates this field when you create the Product Constituent from the Combination Product record. - Constituent Product (
constituent_product__v): (Required) Select the Product, or select Create Product to add a new Product. Manage Product Families provides more information on creating Products. - Name (
name__v): Enter the name of the constituent product, as it should appear when being referenced throughout Vault. - Product Type (
product_type__v): Vault populates this field, based on the product type specified on the associated Product record. To edit this value, edit the Product record.
- Combination Product (
- Select Save.
Combination Product Registrations
When an Inbox Item with a Combination Product is promoted to a Case, Vault uses the information entered in Product Registrations to populate certain fields, calculate expectedness, and generate Submissions.
When setting up Combination Products, we recommend that you add the following Product Registrations:
- Create Product Registrations for the entire Combination Product. For Combination Products with device constituents, you can use the Registered As field to specify whether device constituents should be exported in E2B files generated for that jurisdiction.
- Create additional Product Registrations for each Product Constituent. You can designate which constituent is the Primary Mode of Action (PMOA) using the PMOA field on the Product Registration, which is used to designate the primary Case Product in Combination Product Cases.
Note: Ensure each Combination Product is set up with a Product Registration designating the Product Constituent that is the PMOA. The PMOA registration is used to generate Submissions involving the Combination Product using the appropriate ICSR report type.
Add a Combination Product Registration
- Go to the Product for which you want to add the Product Registration.
- Expand Registrations and then select Create.
- On the Create Product Registration page, complete the appropriate fields.
- Select Save.
Product Registration Fields
| Field | Description |
|---|---|
| Organization ( organization__v) |
Vault automatically populates this field with a reference link to the Organization on the Product parent record. If the Registration Holder/Applicant field is blank, Vault snapshots this field to the Registration Holder field on a Case Product. |
| Product ( product__v) |
Vault automatically populates this field with a reference link to the parent Product record. |
| Product Constituent ( product_constituent__v) |
The Product Constituent for which this registration applies. Vault Safety populates this field when you create the Product Registration from the Product Constituent record. |
| Product Type ( product_type__v) |
Vault populates this field with the product type of the Product parent record. |
| Combination Type ( combination_type__v) |
If the product is a combination product, select the combination type. Vault snapshots this field to the Case Product and the information is used in report generation for the FDA VAERS E2B(R3) format. |
| Registration Name ( name__v) |
(Required) Enter a name for the Product Registration. Vault Safety references the registration using the name that you enter in this field. |
| Registration Number ( registration_number__v) |
Enter the product authorization or application number for the country where the product is marketed. For U.S. Registrations, ensure that the value you enter in this field adheres to the FDA E2B format requirements for element B.4.k.4.1 (Authorisation / Application Number). Vault snapshots this field to the Case Product and is used in report generation for E2B, FDA MedWatch 3500A, and PADER formats. |
| Registration Applicant/Holder ( registration_holderapplicant__v) |
Vault snapshots this field to the Registration Holder field on Case Products. If this field is blank, the value in the Organization field is snapshot instead. |
| MAH ( reporting_organization__v) |
This field may also be named "Reporting Organization" depending on your Admin's configuration. If you have a Marketing Authorization Holder (MAH) that manages your ICSR reporting obligations for this registration, select the Organization. Selecting an Organization in this field creates an MAH Distribution List, and thereby a reporting obligation, for this registration. Note: Removing the last remaining MAH/Reporting Organization from an MAH Distribution List will also delete the MAH Distribution list. Warning: Use caution when setting this field. Reporting Obligations are for Distributions only and override agency submission rules. Do not select an Agency such as the FDA or EMA. |
| Transmission Profile ( transmission_profile__v) |
Select the Transmission Profile Vault should use when automatically generating Submissions for this registration. We recommend setting this field when you have a Transmission Profile corresponding to this reporting destination and report type. |
| PMOA ( pmoa__v) |
Select Yes or No, depending on whether the product is designated as the Primary Mode of Action (PMOA). The product designated as the PMOA is set as the primary Case Product on Cases concerning the Combination Product. The reporting rules engine uses the PMOA registration to match the Transmission Profile when generating Submissions for Cases involving the Combination Product. |
| Registration Date ( registration_date__v) |
Enter the date when the product was registered. This field is for reference only. |
| Registration Type ( registration_type__v) |
Select the registration type. This field is used in report generation for FDA MedWatch 3500A and PADER formats. This field is needed to correctly match Transmission Profile Scope records for any Organization which has multiple Transmission Profiles for the same destination Agency. |
| Country ( country__v) |
Select the country where the product is registered and authorized. Vault snapshots this field to the Registration Country field on a Case Product and is used in report generation for E2B formats. |
| Route of Administration ( route_of_administration__v) |
Select the route of administration TermID code. Vault snapshots this field to the first Case Product Dosage record for the Combination Product. |
| Compounding Type ( compounding_type__v) |
If the product is a compounded product, select the compounding type. Vault snapshots this field to the Case Product and is used in report generation for E2B formats. |
| Agency ( agency__v) |
Based on the Country selected on the Product Registration, Vault automatically populates this field with the Agency assigned jurisdiction over that country. If configured, reporting rules generate Submissions to this Agency when a Case Product references this Product Registration. |
| Local Datasheet ( datasheet__v) |
Select the Local Datasheet for this product registration. A Local Datasheet is specific to a country or region, listing expected adverse events that apply to that product registration. Datasheets are used to automatically detect expectedness for an adverse event and the suspect or interacting Case Products. |
| Registered As ( transmission_product_type__v) |
Select the product type for this registration from the following options:
Vault snapshots this field when generating Transmissions for this registration, then uses that value to determine whether Device-type Combination Product Constituents are exported in E2B transmissions. See Exclude Device Constituents from E2B Exports for more information. When generating an FDA 3500A form for a non-Combination Company Product, this field determines which section of the form is populated, as follows:
For information on how the product type for a registration is used when evaluating reporting rules, see the Product Registration Type rule parameter. This field does not appear on layouts by default, but can be added to Transmission layouts by your Admin. Depending on your Admin's configuration, this field may be named Transmission Product Type. |
| Default Registration ( default_registration__v) |
Designates the registration as the most current or commonly used registration for the selected country. If the registration is the most commonly used for the selected country, select the checkbox. During data entry, in the Case Product Registration field, this registration is prioritized in the picklist, though all active Product Registrations remain available for use. |
Make a Combination Product Registration Inactive
You can set a Product Registration record to a Deleted state type so that the Safety Rule Engine no longer considers it when determining a Case’s reportability. With this setup, if the Product Registration was used in any existing Cases, it is available for follow-up scenarios.
To use this feature, your Admin must enable Inactivate Product & Study Registrations.
Complete the following steps to make a Product Registration inactive:
- In the Product Registration record, select the State button and select Deprecated from the picklist. Depending on your Admin’s configuration, the inactive state may have a different label.
- In the Change Object Status dialog, select Yes.
Similarly, if you need to reactivate the record, complete the steps detailed above but select Active from the picklist.
How to Open a Case for Combination Products
- Create an Inbox Item (manually or through import).
- For manual creation, select the Combination Product as the case product. You must select the Combination Product and not a Product Constituent to leverage the full capabilities of combination products.
- Promote the Inbox Item to a Case.
Result
Once you promote to Case, each Combination Product break aparts into its constituents and Vault adds each Product Constituent as a Case Product. The following occurs:
- Product Registrations for the Product Constituents are snapshotted to the Case.
- The Product Registration for the Combination Product is linked on each Case Product.
- For each Product Constituent, the following details are populated:
- Product Type and Product (Coded) name are snapshot from the Product Registration.
- Indications are snapshot from the Inbox Item to each Case Product.
- Dosages are snapshot from the Inbox Item to each non-Device-type Case Product.
Primary Case Product Designation for Combination Products
Upon Case promotion, Vault automatically designates the primary Case Product, using the following logic:
- If there is a Product Constituent set as the PMOA on the Product Registration, Vault Safety automatically designates that product as the primary Case Product.
- If there are no PMOA Product Constituents, the Case Product generated first becomes the primary.
Product Constituents are set as PMOA through the PMOA field on the Product Registration.
Once the primary Case Product is determined, Vault attaches a Case Assessment to it. For E2B-imported Inbox Items containing Combination Products with attached Case Assessments, upon Case promotion Vault copies the imported Case Assessments to the Product Constituents.
Note: There is a limitation where, when promoting an E2B-imported Inbox Item with a Combination Product to a Follow-Up Case, the imported Case Assessments and Case Assessment Results are not being copied to the Follow-Up Case. This limitation will be addressed in a future release.
Enter Combination Product-Related Case Data
Vault Safety includes data entry capabilities that support combination products and device constituents, including device-specific product fields. You can classify the device report type (malfunction, public health risk, or both) and add additional combination product-related information for the reason a Follow-Up Case was created.
When a Combination Product Registration is selected for a Case Product Constituent, Vault copies all of the registration details to the Case.
The following list outlines the specific sections that you can use to enter data for Cases concerning combination products with device constituents:
- The Device Details section on the Case object.
- The Device Information section on the Case Product object.
Combination Product E2B Export
Vault Safety supports generating compliant FDA E2B(R2) and EMA E2B(R3) files for combination products, including device-related elements.
For FDA E2B(R2), there is a separate section appended to the file for combination product elements. For EMA E2B(R3), combination product elements are nested under other sections.
Exclude Device Constituents from E2B Exports
By default, E2B files generated for a Combination Product Case include both Device-type and Drug-type Product Constituents.
Because certain jurisdictions do not accept combination product submissions, you can configure a Transmission to exclude Device-type product constituents from E2B files generated for Combination Product reports.
Prerequisites
Ensure the following fields appear on layouts and the appropriate user groups have edit permissions:
- The Registered As field on Product Registration layouts and the Transmission Product Type field on Study Registration layouts.
- Depending on your Admin’s configuration, this field may be named Transmission Product Type on Product Registration records.
- The Exclude Device Constituents by Default field on Transmission Profile layouts.
Exclude Devices for Submissions
To exclude device constituents, set the Registered As field on Product Registrations and the Transmission Product Type field on Study Registrations to any Transmission Product Type value other than “Combination Product”. If left blank, Vault continues to transmit device constituents by default.
When evaluating reporting rules and generating Submissions, Vault looks at the Transmission Product Type on the Product or Study Registration being used to generate each Submission.
When evaluating whether to exclude the device constituents for a given jurisdiction, if there are multiple registrations, Vault applies the following logic:
| Transmission Product Type Setting | E2B Generation |
|---|---|
| "Combination Product" or blank on any Registration | All Product Constituents are transmitted, including devices. |
| Any value other than "Combination Product" or blank on all Registrations | Device-related data elements are omitted. Only non-device Product Constituents are transmitted. |
If you’re submitting a report to a destination where a product is not registered, you can use the Exclude Device Constituents by Default field on a Transmission Profile to specify how Vault should treat products in unregistered jurisdictions.
Exclude Devices for Distributions
The Transmission Product Type on registrations are not used for Distributions. To omit device constituents, select the Exclude Device Constituents by Default field on the Transmission Profile corresponding to the Distribution.
Frequently Asked Questions About Combination Products
How does Vault automatically calculate Expectedness for Combination Product Cases?
For each Case Assessment created for a Combination Product Constituent, Vault automatically calculates the expectedness using the Datasheets related to the associated Product.
Can I set up Watchlists for a Combination Product?
Yes. You can create watchlists for Combination Products. When you add a Combination Product to a watchlist, that watchlist applies to any Case with Product Constituents that belong to that Combination Product.
However, if you create a watchlist for an individual Product that happens to be a Product Constituent, the watchlist will only track Cases involving the standalone Product.
Configure Adverse Event Watchlists provides more information about how to set up watchlists.
How are Submissions generated for Cases concerning combination products?
Vault Safety uses Combination Product Registrations to evaluate reporting obligations and the target health agency for Submissions. Vault assigns the appropriate Transmission Profile and due dates for Submissions, based on the primary product type, report type, and product registration country.
For example, for a Case concerning a Combination Product combining the drug Cholecap with the biologic Labrinone, both registered in the United States, Vault Safety generates the following Submissions:
- For the drug Cholecap, Vault generates a Submission using the FDA E2B(R2) format and the CDER Transmission Profile.
- For the biologic Labrinone, Vault generates a Submission using the FDA E2B(R2) format and the CBER Transmission Profile.
How are Case reporting due dates calculated for combination products?
For Combination Products with a drug or biologic constituent and a device constituent, Submissions adhere to the following due dates, based on the receipt date:
- For a Case classified as a public health risk, Vault generates a Submission due in 5 days.
- For a non-serious Case classified as a malfunction but not a public health risk, Vault generates a Submission due in 30 days.
- Otherwise, Vault generates a Submission due in 15 days.
Reporting Rule Sets provides more information on the reporting timelines that Vault Safety uses.
Do we support FDA 3500A reporting elements for combination products?
Yes. Vault Safety generates compliant FDA 3500A forms for combination-type product submissions, including the required Reporting Elements for Combination Products.
FDA 3500A Generation Data Mapping provides more information about the 3500A fields that Vault Safety populates.
Do we support Device Only for combination products?
No. A combination product is a product containing multiple constituents and any combination of drug, device, and/or biologic components. Vault Safety does not support configuring combination products as device only.