# Presentation: 833085

## BUNDLING In Vitro Diagnostic Devices

- The Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)
- Presented by
- James V. Callaghan

## EXAMPLES

- Family member of instruments
- when the same analytical and clinical data can be used for all the analytes/instruments referenced
- multiple analytes (e.g., recognized test panels or profiles)

## EXAMPLES 

- Recognized test panels or profiles
- Centers for Medicare and Medicaid Services (CMS) reimbursement national coverage book
- include profiles such as lipid profiles and liver function tests.

## EXAMPLES 

- You should not bundle
- multiple analytes, or across test panels or profiles, if they present disparate scientific and clinical issues.

## EXAMPLES

- Antimicrobial Susceptibility Testing (AST) systems should include only one drug,
- you may bundle gram-negative and gram-positive uses
- as well as different methods for reading the results (e.g., semi-automated, fully automated, or inoculation (direct, growth, other)).

## EXAMPLES 

- Two other examples of panels that could be bundled into one submission include:
- (1) TORCH (Toxoplasma, Rubella, CMV, and Herpes) panel
- (2) Drugs of abuse (cocaine, THC, opiates, methamphetamine, and amphetamine) panel

## EXAMPLES

- For any type of premarket submission
- assayed controls and/or calibrators may be bundled with an assay.
- Also, controls or calibrators used for multiple assays (and/or multiple platforms) may be bundled to cover their use in all of the assays.

## Multiple Reagents

- You may bundle multiple reagents that are intended to be used together to obtain a profile (e.g., a cardiac panel (troponin, CK MB, and myoglobin)) into a single submission.
- Whereas a single reagent could be submitted as a single submission, there are situations where multiple reagents have many commonalities
- and the additional information to support each of the reagents is minor and does not require substantial review resources.

## Multiple Reagents 

- Reagents generally should not be bundled
- if the reagents require separate preclinical data, clinical data, or
- downstream processing information that would preclude efficient review of the submission.

## Multiple Intended Uses

- You generally should not bundle multiple intended uses of a single test system (or indications for use such as professional and over-the-counter (OTC) use)
- Can not bundle assays intended for the detection of Neisseria meningitidis, and Neisseria gonorrhoea

## Multiple Intended Uses 

- There may be cases, when you could bundle different intended uses.
- you may bundle N. gonorrhoea and Chlamydia trachomatis if the same clinical trial using the same specimen type and same population are used.

## Sample Matrix 

- Bundling when similar matrices (e.g., serum and plasma).
- You should not bundle dissimilar sample matrices (e.g., hair and/or saliva with serum and/or plasma).

## Replacement Reagents

- The Replacement Reagent policy has been updated to supersede, “Data for Commercialization of Original Equipment Manufacturer, Secondary and Generic Reagents for Automatic Analyzers” we will discuss that later.
- There will be no fees associated with the RR-Policy

## Process for Multiple Markers that Require a PMA

- For a PMA submission where one analyte (e.g., hepatitis B virus) may have multiple markers
- The first marker may be submitted as an original PMA.

## Process for Multiple Markers that Require a PMA

- After the original PMA is approved, the other markers may then be submitted as individual 180-day PMA supplements to the original PMA.
-  All data should be generated from the same clinical trial.

## In Vitro Diagnostic Devices Regulated by CBER

- As with devices reviewed by CDRH, some devices reviewed at CBER are marketed as 510(k) products, while others are marketed as PMA products.
- Reagents and test kits used to test the blood supply are regulated as licensed biological products.

## In Vitro Diagnostic Devices Regulated by CBER

- When the reagents and instruments can be used together and significant portions of multiple individual submissions would contain the same information,
- You may bundle different articles, even though one article is regulated under the device authorities and the other under the BLA authorities.
- The BLA user fee and review time would apply when making such a submission.
- Please identify the submissions to be bundled in the cover letter submitted with the applications.

## In Vitro Diagnostic Devices Regulated by CBER

- In cases involving a BLA or efficacy supplement where one submission in a bundle is delaying approval of the others,
- CBER may discuss mechanisms for “de-linking” the problem submission so that the others can be finalized.
- The remaining portion of the bundle would be handled at a later date

## Bundling Procedures

- As is true for any 510(k), you must provide all the information required by 21 CFR § 807.87.
- You should also include an “Indications for Use” form for each device in the submission

## Bundling Procedures

- Bundling in one 510(k) a change that affects more than one previously cleared device
- You should also provide updated Indications for Use forms that address all the devices in the submission, if individual devices will have differing indications for use.

## Bundling Procedures

- When bundling devices of the same generic type in a PMA, you should ensure that you provide all the information required by 21 CFR § 814.20 to support approval for each of the devices, including labeling that addresses all of the devices.

## Bundling Procedures

- As stated earlier, bundling multiple indications for use in one PMA is generally not appropriate.
- If, however, much of the data needed to support approval of the devices would be the same you may submit one PMA for multiple indications.
- You should ensure that the supporting information and the labeling address all the indications.

## Bundling Procedures

- When bundling a change(s) that affects more than one PMA,
- you may submit all the required information to support approval of the modification, including any associated labeling changes that result from the modification in one PMA supplement.
- In the cover letter for the supplement, you should identify the other affected PMA(s).

## Bundling Procedures

- If the affected PMAs are reviewed by different divisions, you may still be able to bundle the change(s) in one PMA supplement.
- In the Annual Report, reference approved PMA(s)

## Bundling Procedures

- The same cover letter should be used for each copy and should clearly indicate that the same change(s) is being made to each of the affected PMA(s).
- The cover letter should identify all of the affected PMA(s).

## Bundling Procedures

- Bundling a change that affects a device with 510(k) and PMA indications
- When submitting a change to a device that affects both a previously cleared 510(k) and an approved PMA, you should submit a PMA supplement and reference the cleared 510(k).
- In this situation, the PMA review time and user fee would apply for the submission.

## Bundling Procedures

- In general, a 510(k) device should not be bundled with a PMA device.
- If, however, you have devices that are used together in a procedure or that are part of a system, bundling may be appropriate.
- PMA should include all the information needed to support both approval and clearance of the devices when used as indicated.

## Bundling Procedures

- If a submission includes a device or indication that should not be bundled.
- the agency will notify the applicant in writing and request that the applicant withdraw the device or indication from the bundled submission.
- Upon issuance of this letter, the application will be placed on hold.

## Bundling Procedures

- The applicant may resubmit the device or indication for use in a separate submission,
- withdraw the device or indication for use (the review of the rest of the submission will continue),
- withdraw the entire application,
- or appeal the decision.

## Bundling Procedures

- You should refer to 21 CFR § 10.75, which outlines the framework for internal review of decisions.
- While the appeal is under review, the submission will remain on hold (to ensure appropriate review of the submission and efficient use of resources).

## Bundling Procedures

- FDA strongly recommends that bundling occur before the application is submitted to the agency.
- Submitters may withdraw a device(s) (or indication for use) from a bundled submission for any reason.

## Bundling Procedures

- You may resubmit the device(s) or indication for use in a new application.
- Resubmission of a premarket submission for a withdrawn device or indication for use will require payment of the fee applicable to the type of submission.

## Contacts for General Questions

- ODE, CDRH
- Robert Gatling Program Operations Staff
- 301-594-1190, ext. 140 or by email to RRG@CDRH.FDA.GOV
- OIVD, CDRH
- Sousan Altaie 301-594-3084, ext.145 or by email to SSA@CDRH.FDA.GOV
- CBER
- Sheryl Kochman 301-827-6123 or by email to KOCHMAN@CBER.FDA.GOV

## Specific Questions

- Division Contacts
- DCTD
- Jean Cooper, Alberto Gutierrez, Carol Benson, Jim Callaghan - **301-594-1243**
- DMVD
- Sally Hojvat, Freddie Poole  - **301-594-2096**
- DIHD
- Joseph Hackett, Josephine Bautista, Maria Chan
-     **301-595-1293**