ISPE Annual Meeting 29 October – 1 November 2017 San Diego, CA · 2017-10-09 · ISPE Annual Meeting 29 October – 1 November 2017 San Diego, CA 5 Report Types 1. 5‐Day Reports

ISPE Annual Meeting29 October – 1 November 2017

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Post‐Marketing Safety Reporting (PMSR)

Challenges and Successful Practices for Combination Products

Objective – Session Goals

• Summary of the final rule

• Interpretation for combination products approved as Drug/Biologics

• Organizational Preparedness

• Key Challenges & Solutions

• Scenarios for Drug/Biologic and Device application types


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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 of product

Summary of the final rulePost Marketing Safety Reporting (PMSR):

• Safety

• Efficacy and Effectiveness

• Ease of use

Drug delivery systems / platforms, on‐body systems, Infusion Pumps, Wound Care Combination Products, Inhalers, Transdermal Patches

Prepare Plan Change management Implementation


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Expectation

• Combination Product as a “Whole” or as a system

• “Single” report with all the relevant information

• Risk based review, prioritization and reporting

• One integrated set of reporting timelines

• Reported through one system to relevant division

• Based on familiar processes, systems and requirements

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

Nothing New !!! Clarity


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Who is responsible for what?

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

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

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

• ONLY cpa – information sharing requirements

Final 21 CFR Part 803 revision

regarding e-MDR becomes effective

2002 ‐ 2005 2009 ‐ 2010 2013 2014 2015

Proposed 21 CFR Part 4 (Subpart B) on Post-

Marketing Safety Reporting for Combination Products (2)

FDA Concept Paper on Post-Marketing Safety

Reporting for Combination Products

(1)

Final 21 CFR Part 4 (Subpart B) and any associated guidance document(s) pending

Stakeholder / Industry Comments on Proposed 21

CFR Part 4 (Subpart B)

Final 21 CFR Part 4 (Subpart A) on Current Good Manufacturing Practices (cGMP) for

Combination Products

Draft Guidance on cGMP for Combination

Products

(1) Concept Paper: Post-Market Safety Reporting for Combination Products FDA Office of Combination Products; 2005.

(2) Federal Register / Vol. 74, No. 189 / Thursday, October 1, 2009 / Proposed Rules / Docket No. FDA–2008–N–0424]

FDA Public

Hearing

Post‐marketing safety reporting for Combination Products

2016 2017 2018

Final 21 CFR Part 4 (Subpart B) Post Marketing Safety

Reporting

Issu

ed Compliance

date July ‘18

Final Guidance on cGMP for Combination

Products

Eff

ect

ive

Timelines


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Report Types1. 5‐Day Reports

2. Malfunction Reports – 30‐Day 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(device 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

Overview of Reporting Requirements for Combination Product Applicants as Required by the Combination Product Postmarketing Safety Rule*

Application Type

Constituent Part ANDA/NDA BLA Device Application

Standard Filing

Requirement

15‐day report (initial & follow‐up)

Field alert report

Periodic report

15‐day report (initial & follow‐up)

BPDR

Periodic report

Malfunction report (initial & supplemental)

5‐day report (initial & supplemental )

Correction or removal report/record

Drug Refer to standard filing requirements Field alert report 15‐day report requirements to be submitted

within 30 days (initial & follow‐up)

Field alert report

Biologic BPDR Refer to standard filing requirements 15‐day report requirements to be submitted

within 30 days (initial & follow‐up) submitted

BPDR

Device Single malfunction report (of available

information) in 15 days or 15‐day initial report

and follow up report

5‐day report (initial & follow‐up )


Periodic report with summary & analysis of 5‐day

& malfunction reports

Single malfunction report in 15 days or 15‐day

initial report and follow up report. 5‐day report

(initial & follow‐up )


Periodic report with summary & analysis of 5‐day

& malfunction reports

Refer to standard filing requirements

*Gray‐shaded boxes indicate current reporting requirements and orange‐shaded boxes indicate new reporting requirements.

ANDA indicates abbreviated new drug application; BLA, biologic license application; BPDR, biological product deviation report; NDA, new drug application.

Application type ‐ Drug/Biologics

For periodic safety reporting of combination products with a device constituent part that received marketing authorization under NDA, BLA or ANDA, the combination product applicant must also include a summary and analysis of the 5‐day (device) reports and 30‐day device malfunction reports that were submitted during the reporting interval.


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Application type ‐ DrugsANDA/NDA 15‐day report (initial & follow‐up)

Field alert report

Periodic report

+ Constituent part : Biologic

• BPDR

+ Constituent part : Device

• Single malfunction report (of available information) in 15 days (AE) or 15‐day initial report

(AE data) and follow up report with device information as available. Clarification: If report is

for a reportable malfunction ONLY – option to submit report in 30 days

• 5‐day report (initial & follow‐up )

• Correction or removal report/record

• Periodic report with summary & analysis of 5‐day & malfunction reports

Application type ‐ BiologicsBLA 15‐day report (initial & follow‐up)

BPDR

Periodic report

+ Constituent part : Drug• Field Alert Report (FAR)

+ Constituent part : Device• Single malfunction report (of available information) in 15 days (AE) or 15‐day initial report (AE

data) and follow up report with device information as available. Clarification: If report is for a

reportable malfunction ONLY – option to submit report in 30 days

• 5‐day report (initial & follow‐up )

• Correction or removal report/record• Periodic report with summary & analysis of 5‐day & malfunction reports


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Application type ‐ DevicesDEVICE 30 day ‐Malfunction report (initial & supplemental)



+ Constituent part : Drug• 15‐day report requirements to be submitted within 30 days

• (initial & follow‐up) • Field alert report (FAR)

+ Constituent part : Biologic• 15‐day report requirements to be submitted within 30 days

• (initial & follow‐up) • BPDR

Organizational Preparedness Drug / Biologic Process Flow ‐ Current

Complaint

PV Group

Quality / Complaint Handling Group

• ICSR & • Periodic Reports

• FAR & • BPDR • Corrections &R


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Organizational Readiness

Drug / Biologic Process Flow – New

Complaint

PV Group

Quality / Complaint Handling Group

• ICSR & • Periodic Reports

• FAR & • BPDR • Corrections &R

Reportable Device Malfunction

Organizational Readiness Device Process Flow – Current / New

Complaint

Quality / Complaint Handling Group 30 day ‐Malfunction report (initial &

supplemental)



FAR

BPDR


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Manual process To be ready & compliant by July

2018

Challenges & Solutions – Data Architecture Issue/Challenge Solution

Data Architecture

Lack of established data structure for Medicinal Product & Medical Device Reporting

Short term solution: Companies could provide data for the other constituent part that is not available in the E2B (drug) or HL7 (device) scheme as unstructured free text data within the narrative section.

Long-term solutions:(i) FDA to revise relevant reporting forms(ii) Industry & FDA work together to establish data architecture and content acceptable to both parties.

• Guidance to Implementation / compliance


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Challenges & Solutions – System InfrastructureIssue/Challenge Solution

System Infrastructure

Integration of independent drug & device reporting systems within companies for meeting combination product reporting rule requirements. Industry infrastructure is not set up to produce a single unified report.

Industry to conduct a gap assessment of their existing global safety applications and Quality system applications

FDA & industry should work together to define the functional requirements for a unified report (ICH E2B (R3), HL7 is a possibility).

• Guidance to Implementation / compliance

CDRH ‐ Updates to FDA’s eMDR Submission

• UDI update: Submitters to only include the DI portion of UDI ‐ D4 field unless the DI is unknown; This update is already in effect.

• Acceptance of new XML formats: Older submission formats will be phased out over one year. This update will take effect June 29, 2017.

• Combination product field: eMDR submission forms will allow more room to include drug information for combination products involved in adverse events. This change will go live on June 29, 2017.

• Device problem codes: FDA Device Problem Codes used for eMDRsubmissions will be harmonized with Annex A of the International Medical Device Regulators Forum’s Adverse Event Reporting terminology document. Existing FDA problem codes accepted in e‐submissions through December 2017. Updates take effect July 7, 2017.


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https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/ReportingAdverseEvents/eMDR–ElectronicMedicalDeviceReporting/ucm475303.htm

CDRH ‐ Updates to FDA’s eMDR Submission

For more information on the precise changes to eMDR, see the implementation package.

Challenges with compliance – 18 months System & Infrastructure

• Guidance content – level of detail is unknown

• Structured data fields unknown (Number / content)

• IT Vendors will need to create / update systems for intake, processing, assessing and submission of new data elements (multiple systems) – 9 to 12 months (parallel development)

• System upgrades, Testing & Validation (Internal) – 6 ‐ 9 months

• Automate information sharing between PV & QA – 6 ‐ 9 months

• Impact Assessment (Global reporting)

• FDA Connectivity updates and validation – 6 ‐ 9 months

It will take a minimum of 12 to 18 months from the final guidance publication to implementation


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Challenges with compliance – 18 months

Other Unknowns

• Volume impact

• Added Compliance risk

• Process / Procedures to be updated

• Budget

• Organizational alignment

• Training

• Talent

Challenges & Solutions – OrganizationalIssue/Challenge Solution

Organizational

Organizational alignment, retraining & resourcing within combination product applicant companies

(i) Differing functional responsibilities(ii) Differences in terminology (iii) Differences in processes & procedures

Industry & FDA work on adoption of terminology that harmonizes device & drug adverse event reporting.

Based on organizational needs & product portfolio, companies should set up a combination product organization that includes personnel from regulatory affairs, safety, quality etc., who are trained on combination product regulations.


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Challenges & Solutions – Business Issue/Challenge Solution

Business

Update/redefinition of relationship between combination product applicants & GMP exempt device manufacturers.

The least burdensome approach to addressing the issue would involve:(i) Combination product applicant, with input from the constituent part supplier, should conduct an assessment of risks related to the interaction of the drug & the device as it relates to the functioning of the combination product.(ii) Institute risk appropriate robust supplier quality agreements that emphasize risks related to device constituent part malfunctions.

Implementation Challenges & SolutionsIndividual Reportable Events (ICSR/MDR)

Issue/Challenge SolutionCase processing

Definition of event & potential discrepancy in number of reports.

(i) Follow application type requirement for reporting(ii) Utilize follow-up reporting as an option to report other constituent part related events.

Non-serious AEs, there is no mechanism for devices, & consequently for the device combination product applicant, to update the drug label in case the non-serious AE is “associated” with the drug.

FDA needs to clarify how non-serious AEs that are “associated” with the drug for device combination product applicants will be communicated to the drug label.


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Issue/Challenge SolutionInvestigation / Malfunction

For device-drug combination products filed under a device application, investigation may not identify the device correlation to the reportable event. In case of a device constituent part malfunction for a drug/biologic-device combination the lack of an AE may not trigger a drug safety report due to not identifying the potential serious injury that may occur should the malfunction reoccur.

Responsible quality & drug safety functions within combination product applicant’s organization need to be trained on identifying drug or device constituent part specific events. Based on organizational needs & product portfolios,

companies should define criteria for identifying events and set up a combination product organization that includes personnel from regulatory affairs, safety, quality, etc., who are trained on combination product regulations.


Issue/Challenge SolutionAggregate ReportsRisk to aggregate reports, safety signaling & risk management due to lack of readiness of safety systems in combination product applicant companies to assess device & drug/biologic labeling.

Within combination product applicant companies processes should be implemented so that teams look at both labels in evaluating expectedness.

Data Sharing processes for 5-day reporting between constituent part applicants.

Processes need to be set up in constituent part applicant companies to trigger marketed product evaluation & communication for events in scope of the notification.


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Issue/Challenge SolutionHeterogeneity of Reporting Requirements: Multiple health authorities

(i) unique data content for FDA in an expedited report submitted to multiple geographies -challenging to meet using a single unified AE database. (ii) Addition of relevant device investigation information to the AE database will trigger unsolicited reports to ex-US health authorities & affects reporting volume. (iii) A product designation may change in the US as a combination product

(i) Processes will need to be developed within organizations to comply with notification of reportable events outside the US for combination products. The process may not be easily amenable to IT solutions & may be manual.(ii) Agency should clarify how device reportability involving similar/same devices apply to device constituents of combination products, and notification of reportable events outside the US need to be addressed given the potential for increased volume of reporting.


Issue/Challenge SolutionHeterogeneity of Reporting Requirements: Multiple health authorities (Continued)

(iv) FDA & certain other geographies require notification of reportable events outside their country. (v) Significant increase in volume of reports in the US - For medical devices, reportable malfunctions that occur outside the US for same or similar products, while this is not the case for drugs/biologics. (vi) Reporting timelines may differ

(i) Processes will need to be developed within organizations to comply with notification of reportable events outside the US for combination products. The process may not be easily amenable to IT solutions & may be manual.(ii) Agency should clarify how device reportability involving similar/same devices apply to device constituents of combination products, and notification of reportable events outside the US need to be addressed given the potential for increased volume of reporting.


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Issue/Challenge SolutionDelays or additional follow-up reporting. For devices first day of awareness is day 1, but for drugs it is day 0. For FAR, the day of awareness is day 1 & submission is required within 3 calendar days.

Alignment of a common ‘day 0’ to introduce consistency in reportability timelines.

Expansion of seriousness criteria to include device malfunctions without patient exposure.

Proposal for Industry: Retraining of organizations (like drug safety & device quality). Processes -malfunctions that need to be reported to drug safety.Proposal for FDA: Provide guidance on how industry should process cases where there is no patient AE & mandatory data fields in the current drug reporting forms will not be available.


Issue/Challenge SolutionMultiple reports Least burdensome approach, the follow-up reporting should

follow the type of constituent part impacted, i.e., full report if the follow-up report is related to a drug & only new information if the follow-up is related to a device.

Differences in constituent part coding nomenclature.

The addition of MedDRA SOC 27 may provide an alternative solution for combination products with a drug/biologic application status for coding for reporting purposes for device related issues. Additional agreement across industry & regulators to use MedDRA coding for all patient codes even for devices may further help gain alignment at least for applications approved as ANDA/NDA/BLA.


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Issue/Challenge SolutionConfusion related to multiplicity of lot numbers associated with constituent parts

Align ICH E2B forms with MDR forms to include specific sections for lot numbers & other product identifiers for drug & device constituent parts.

Lack of clarity on details of device reportable events that need to be included in drug/biologic Periodic Safety Reports

Best practices, like device annex, for overall product safety oversight may be incorporated into the proposed guidance to clarify the contents of device reportable event summaries & analyses in drug/biologic periodic reports. Annex helps customize the reports according to local health authority requirements. For certain device classes quarterly reporting will be an option in the future should they qualify for periodic reporting of malfunctions.

[1] Roman X, Reder R, Barch D, Bano K. An approach to Aggregate Safety Reporting of Drug and Device Constituent Parts of Combination Products. Poster Presentation at DIA. 2015.

Additional Questions ?Follow‐up reports:

– What constituent driven event triggers a follow up?

– Expected contents of the Follow‐up reports?

Interim Solution: RISKS

– Sustainability of interim manual approach?

– Maintain and submit different versions of the ICSR based on differing global combination

product regulations?

– Ability to review data in holistic manner due to lack of structured fields to accommodate

required information?

– Different timing of reports given nuances related to device constituent malfunction

investigations.

Field Actions:

– Industry and Agency readiness

– Global impact

Clinical Trials & Investigational products: What to expect ?


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Information Sharing Requirements (cpa)

Objective: Reportable event gets appropriately submitted to FDA in a timely manner. Primarily applies to cross‐labeled combination products. This applies to constituent part application holders ONLY, not to combination product holders.

• 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

How to be ready for July 2018 • Inventory of combination products (pipeline?)

• Application type

• Reassess compliance / gap assessment for 2018

• Platform approach – consistency

• Establish risk‐based approach to reporting

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

• Organizational / resource changes

• Wait for Guidance – IT / infrastructure changes


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Drug Scenarios 1 (Application – Drug/Biologic) Device constituent as suspected cause of SAE

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 embedded needle causing a serious injury

• Seriousness: Yes

• Labeledness/Expectedness: No

• Causality/Contribution/Association/Relatedness: Device (Pre‐determined RM)

• Malfunction: Yes

• ICSR: Yes – 15 Day report with all available SAE and device details – Option to submit device information either as supplement or in 30 days

• 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


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. The solution is reported to have looked cloudy. Investigation determined product lot did not meet T1 stability criteria.

NOTE: 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 ? Or FAR / BPDR Suffice

• 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* (* if applicable)


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

Example: A pre‐filled syringe (PFS) used to treat an autoimmune disease resulted in NO AE / SAE. An unrelated investigation identified a malfunction (needle material defect in that sample) likely to cause (broken needles / safety failure) serious injury should it recur.

• Seriousness: Likely to cause ? Yes, Labeledness/Expectedness: No

• Causality/Contribution/Association/Relatedness: Device, Malfunction: Yes,

• ICSR: Yes – 15 Day report if information is available or 30 day malfunction report – No AE Data to report

• 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 (* Not applicable – unit)


Device Scenarios 1 (Application type – Device) Device constituent as suspected cause of SAE

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 (Pre‐determined RM)

• Malfunction: Yes

• MDR filing: 30‐day malfunction report

• Field Alert Report Requirement: No, Device remedial action report: No

• Periodic Safety Report Inclusion: N/A


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Device Scenarios 2 (Application type – Device) Drug constituent as suspected cause of SAE

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 a post operative pneumonia requiring hospitalization reported.

• Seriousness: Yes / Labeledness: Yes (in drug label) N/A

• Causality/Contribution/Association/Relatedness: Drug

• Malfunction: No

• MDR filing: 30‐day SAE report (labeledness does not matter – as it does not align with primary application type related reporting requirements)

• Field Alert Report Requirement: No, Device remedial action report: No

• Periodic Safety Report Inclusion: N/A

Key Takeaways• Industry will be ready and compliant – Manual process

• Guidance will help clarify

– Follow‐up report // Details of summary and analysis of 5‐day and 30‐day malfunction reports in the PSUR report // Reportable Malfunction (No AE) in a Drug – Device combination product.

– For Drug PMOA will the seriousness criteria be used and for Device PMOA will the serious injury criteria be used or follow both? or will it be based on whether drug or device is the cause (difficult to determine).

• If forms are updated – appropriate time allocation will be needed for implementation

• Need open channel of communications for discussions


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Readiness for July 2018

• Establish risk‐based approach to reporting • Historical review of data (2 yrs) id SAE / AE profile

• Risk stratification – monitoring vs evaluation

• Cross Functional Team to categorize events ‐ constituent part assignable cause for reportable events*

• Develop reportability rationale

• Update process / procedure to flag them

• Inform the team responsible for reporting

• Provide information to add to narrative for reporting

(*example: autoinjector – injection site abscess, Broke/ embedded needles, premature delivery of needle, counterfeit product, sterility breach confirmed)

References• https://www.fda.gov/CombinationProducts/default.htm

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

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

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

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

• http://combinationproducts.com/wp‐content/uploads/2017/07/Final‐Postmarket‐Safety‐Reporting‐White‐Paper‐5July2017.pdf

• Roman X, Reder R, Barch D, Bano K. An approach to Aggregate Safety Reporting of Drug and Device Constituent Parts of Combination Products. Poster Presentation at DIA. 2015.

• Medical Device Reporting for Manufacturers, Guidance for Industry and FDA Staff, 08 November 2016, pp. 4‐5.

• Postmarket Surveillance under Section 522 of the Federal Food, Drug, and Cosmetic Act. U.S. Department of Health and Human Services FDA, CDRH,

• Office of Surveillance and Biometrics (OSB), Division of Epidemiology. Guidance Issued on May 16, 2016.


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Dr. Khaudeja Bano, MD, Senior Medical Director,

Abbott [email protected]