The Impacts of FDA Combination Product Rulings on Medical Devices

Khaudeja Bano Arlington, VA - June 14th 2017

15th Product Complaint Congress for Life Sciences

Disclaimer

Speaker’s personal opinion and interpretation and does not reflect any company or organizational position

Scenarios discussed are hypothetical and do not reflect any specific product or class

• Safety, Efficacy and Effectiveness

• Ease of use

• All populations – protected populations

Drug delivery systems / platforms, on-body systems, Drug Eluting Stents, Infusion Pumps, Photosensitizers, Orthopedic Combination Products, Wound Care Combination Products, Inhalers, Transdermal Patches, Intraocular Implants and Drug Eluting Beads

http://www.mddionline.com/article/global-drug-device-combination-products-expected-grow-1151b-2019

Our Objective

Regulations - FDA

The cGMP Final Rule for combination product addresses how to comply with CGMP requirements for co-packaged and single-entity combination products.

It recognizes the multiple quality systems and addresses how to maintain them for combination products

[21 CFR 4.4(b)(1) and (b)(2)].

Rule was effective 22 July 2013

(Drug) cGMP

(Device)

QS

Combination product

compliance

(Drug) cGMP + • Sec. 820.20. Management responsibility. • Sec. 820.30. Design controls. • Sec. 820.50. Purchasing controls. • Sec. 820.100. Corrective and preventive action. • Sec. 820.170. Installation. • Sec. 820.200. Servicing

(Device) QS + • Sec. 211.84. Testing and approval or rejection components, drug product containers,

closures • Sec. 211.103. Calculation of yield. • Sec. 211.132. Tamper-evident packaging requirements for (OTC) drug products • Sec. 211.137. Expiration dating. • Sec. 211.165. Testing and release for distribution. • Sec. 211.166. Stability testing. • Sec. 211.167. Special testing requirements. • Sec. 211.170. Reserve samples.

Combination Product types

A combination product as defined in 21 CFR § 3.2(e), as a product comprised of any combination of a drug and a device; a biological product and a device; a drug and a biological product; or a drug, device, and a biological product.

(1) Single entity combination product

(2) Co-packaged / Kits

(3) Cross-Labeled Products

Key Focus Areas

• Risk Management

• Drug / Biologic considerations for validation testing

• Dependencies between the constituent parts

• Timing of Validation and verification studies

• Clinical trial readiness

• Change management / controls

• Pre / post – market change controls

• Human Factors

Expectation

• Product as a “Whole” or as a system

• Risk based review, prioritization and reporting

• One report with all the relevant information

• One integrated set of reporting timelines

• Reported to one system

Post Market Safety reporting (PMSR) Final Rule

Applies to all combination product applicants (CPA) and constituent part applicants (cpa) of combination products

A. Application type drives primary reporting

B. Constituent parts determine additional reporting requirements

• Data sharing requirements

• Data retention

Key Timelines

Leverage existing industry experience, Consistency and “single-report” with the whole story

• Comply with requirements associated with application type (Jan 2017)

• Additional requirements to be met by July 2018

Report Types 1. 5-Day Reports

2. Malfunction Reports

3. Correction or Removal Reports

4. Field Alert Reports (combination product with drug constituent part)

5. 15-Day Reports that can be filed in 30 days(combination product with drug or biological constituent part) and

6. Biological Product Deviation Report (BPDR) (combination product with biological constituent part)

Periodic safety reporting of combination products with a device constituent part for new drug application (NDA), biologic license application (BLA) or abbreviated new drug application (ANDA),

• Summary and analysis of the 5-day [device] reports and 30-day device malfunction reports that were submitted during the reporting interval.

Drugs: 21 CFR 310 & 314 / Medical Devices: 21 CFR 803 / Biologics: 21 CFR 600 & 606

Who is responsible for what?

• CPA and cpa – All PMSR requirements associated with application type

• ONLY CPA – (+) Additional requirements related to constituent part

• ONLY cpa – information sharing requirements

Combination product applicants (CPA) and constituent part applicants (cpa)

Information Sharing Requirements (cpa)

• Death or serious injuries - 21 CFR 803.3 and

• Adverse experiences - 21 CFR 314.80(a) or 600.80(a)

Within five calendar days

– Forward information

– One‐time forwarding of information per event

Set up processes / procedures / quality agreements

Recommended Best Practices

• Inventory of combination products (pipeline?)

• Application type

• Reassess compliance / gap assessment for 2018

• Platform approach

• Establish risk-based approach to reporting

• Risk management – constituent part assignable cause of adverse event / malfunction

• Organizational / resource changes

• Guidance – IT / infrastructure changes

Device Scenarios 1 Device constituent as suspected cause of SAE

Application type – Device Event is assessed for submission as an MDR. In this scenario, the MDR would primarily contain device information elements. Example: While using a drug-eluting stent to treat a coronary artery stenosis the stent failed to deploy resulting in the need to remove and deploy another stent causing procedural complications due to prolongation of procedure. • Seriousness: Yes • Labeledness: No (not in IFU or drug label). • Causality/Contribution/Association/Relatedness: Device • Malfunction: Yes • MDR filing: 30-day malfunction report (only if this is a non-labeled event) • Field Alert Report Requirement: No, Device remedial action report: No • Periodic Safety Report Inclusion: N/A

Device Scenarios 2 Drug constituent as suspected cause of SAE

Application type – Device Event is assessed for submission as an MDR. In this scenario, the MDR would primarily contain device information elements. Example: While using a drug-eluting stent to treat a coronary artery stenosis there was an infection. • Seriousness: Yes • Labeledness: Yes (in drug label). • Causality/Contribution/Association/Relatedness: Drug • Malfunction: No • MDR filing: 30-day malfunction report – Does labeledness matter? • Field Alert Report Requirement: No, Device remedial action report: No • Periodic Safety Report Inclusion: N/A

Drug Scenarios 1 Device constituent as suspected cause of SAE

Application type - drug/biologic.

Report where the device is the suspected cause of the event is assessed for submission as an ICSR

Example: An autoinjector used to treat an autoimmune disease resulted in a needle misfire / broken embeded needle causing a serious injury .

• Seriousness: Yes,

• Labeledness/Expectedness: No

• Causality/Contribution/Association/Relatedness: Device

• Malfunction: Yes

• ICSR: Yes – 15 Day report with all device details

• Field Alert Report Requirement: No (if drug constituent part is involved) / Biologic Product Deviation Report: No (if biologic constituent part is involved) / Periodic Safety Report Inclusion: Yes

Drug Scenarios 2 Drug / Biologic constituent as suspected cause of SAE

Application type - drug/biologic.

Report where the drug/biologic is the suspected cause of the event is assessed for submission as an ICSR

Example: A pre-filled syringe (PFS) used to treat an autoimmune disease resulted in an allergic reaction requiring hospitalization. Additionally, the solution is reported to have looked cloudy. Upon investigation it was determined that the product did not meet stability criteria at time point T1. Please note that in this scenario, device related causes are ruled out (e.g. no impact from leaching of silicone from the PFS walls and associated denaturing of the product).

• Seriousness: Yes, Labeledness/Expectedness: No

• Causality/Contribution/Association/Relatedness: Drug

• Malfunction: No, ICSR: Yes – 15 Day report

• Field Alert Report Requirement: Yes (if drug constituent part is involved) / Biologic Product Deviation Report: Yes (if biologic constituent part is involved) / Periodic Safety Report Inclusion: Yes

References

Final rule and guidance • https://www.fda.gov/CombinationProducts/default.htm

• https://www.fda.gov/RegulatoryInformation/Guidances/ucm126198.htm

CGMP guidance for medical products: • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulat

oryInformation/default.htm

• http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm

• http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/default.htm