Postmarket Adverse Event Reporting and cGMP: What You Absolutely Need to

Know Panelists: Khaudeja Bano, MD, Senior Medical Director, Abbott Beverly Lorell, MD, Senior Medical & Policy Advisor, King & Spalding LLP Katlin McKelvie Backfield, Attorney at Law and Consultant, Backfield PLLC Moderator: Steve Niedelman, Lead Quality Systems and Compliance Consultant, King & Spalding LLP

Current Good

Manufacturing Practice

Requirements for

Combination Products

Katlin McKelvie Backfield

www.backfieldpllc.com

June 8, 2017

Regulatory History

Draft guidance (October

2004)

Proposed Rule

(September 2009)

Public workshop (January

2010)

Final rule (January

2013)

Draft guidance (January

2015)

Final guidance (January

2017)

Final Rule Issued January 2013

• Added 21 CFR Part 4

• Does not impose any new substantive manufacturing requirements; clarifying in nature

• Overarching principle: constituent parts retain their regulatory status after they are combined

• Focuses on how to demonstrate compliance with CGMP

• Provides two options to combination product manufacturers for demonstrating compliance with CGMP requirements

Regulatory Framework for Compliance

• Combination product manufacturers can demonstrate compliance with either: • All CGMP regulations applicable to each constituent part; or • “Streamlined approach”: Either drug GMP or device QSR;

and specified provisions from the other of the two sets of requirements (GMP or QSR); and requirements specific to biological products and HCT/Ps

• Constituent parts that are manufactured at a separate facility from the other constituent parts to be included in a combination product must comply with CGMP applicable to that constituent part

Option 1: Drug CGMP-based streamlined approach: CGMP + select provisions of QSR

If the combination product includes device and drug constituent parts, and the combo product manufacturer chooses to comply with drug CGMP, the following provisions of the device QSR must be satisfied:

• Section 820.20 (management

responsibility) • Section 820.30 (design controls) • Section 820.50 (purchasing controls) • Section 820.100 (corrective and

preventive action) • Section 820.170 (installation) • Section 820.200 (servicing)

Option 2: Device QSR-based streamlined approach: QSR + select provisions of drug CGMP

If the combination product includes both device and drug constituent parts, and the combo product manufacturer chooses to comply with QSR, the following provisions of the drug CGMP regulations must be satisfied:

• Section 211.84 (testing and approval or

rejection of components, drug product containers, and closures)

• Section 211.103 (calculation of yield) • Section 211.132 (tamper-evident packaging

requirements for OTC human drug products) • Section 211.137 (expiration dating) • Section 211.165 (testing and release for

distribution) • Section 211.166 (stability testing) • Section 211.167 (special testing requirements) • Section 211.170 (reserve samples)

Streamlined approach: Biological products and HCT/Ps

If the combination product includes: • a biological product constituent part,

must also comply with requirements applicable to that biological product if it were not part of a combination product;

• an HCT/P, must also comply with all current good tissue practice requirements (including donor eligibility requirements in part 1271) if it were not part of a combination product

Final Guidance Issued January 2017

• General considerations, definitions, terminology • E.g., guidance relating to investigational products,

convenience kits

• Discussion of the select drug CGMP and device QSR regulatory provisions manufacturers must demonstrate compliance with under the streamlined approaches

• Discussion of requirements applicable to biological products and HCT/Ps

• Examples of three types of combination products: prefilled syringe; drug-coated mesh; drug-eluting stent

Case Study: Antibiotic Bone Cement

•Factual scenario

•Choice of options to demonstrate compliance with CGMP

•Considerations for ensuring compliance with CGMP

What’s Next?

• Section 3038 of 21st Century Cures Act requires FDA to publish a proposed list of combination products and manufacturing processes for which: • GMP requirements may vary from 21 CFR Section

4.4; or • the requirements of Section 4.4 can be satisfied

through alternative or streamlined mechanisms.

• Proposed list must be published within 18 months

• After public comment period, FDA must publish a final list in the Federal Register and periodically review it

Postmarket Adverse Event Reporting:

Overview of the New Rule

Beverly Lorell, MD Senior Medical & Policy Advisor FDA & Life Sciences Group King & Spalding

The Final Rule

• On December 20, 2016, FDA published a final rule – “Postmarketing Safety Reporting for Combination Products” – that is codified at 21 CFR part 4 subpart B. (81 Fed. Reg. 92603)

― Effective date: January 19, 2017

― Some provisions have a compliance date later than effective date

― Accessible at https://www.federalregister.gov/documents/2016/12/20/2016-30485/postmarketing-safety-reporting-for-combination-products

Background

• No prior regulations specific to postmarketing safety reporting (PMSR) for combination products

• Public hearing (November 25, 2002) and public workshops (July 8, 2003 and January 10, 2010)

• Proposed Rule issued on October 1, 2009

• Common themes for both FDA and industry

― Consistency and clarity for PMSR for combination products

― Reduction of unnecessary duplicative reporting

Purpose

• To describe PMSR requirements when two or more products (drugs, devices, and/or biological products), which are referred to as constituent parts, comprise a combination product and the combination product or its constituent parts have received FDA marketing authorization.

― Definition of combination product has not changed (See 21 CFR 3.1)

― Rule does not apply to investigational combination products

Obligations – Combination Product Applicant

• Definition: Entity that holds the application for the combination product that was authorized for marketing (21 CFR 4.101)

• Must comply with safety reporting applicable to the classification and type of authorization of the combination product, i.e.,

― NDA or ANDA

― Device application (PMA, 510(k), de novo classification, HDE, PDP)

― BLA

• Also must submit certain additional reports specified in the rule based on the constituent parts

Obligations – Constituent Part Applicant

• Definition: Entity that holds application to market a drug, device, or biological product as a constituent part of a combination product

― The constituent parts of a combination product are marketed under applications held by different applicants

• Must comply with safety reporting applicable to the type of authorization of the constituent part

• Must share certain information with other constituent part applicants

Required Reports - All Applicants

• Both combination product applicants and constituent part applicants must comply with all of the PMSR requirements based on the marketing authorization of the product. See 21 CFR 4.102(b)

― Device applications: 21 CFR parts 803 and 806

― Drug (NDA or ANDA): 21 CFR part 314

― Biological product (BLA): 21 CFR parts 600 and 606

Required Reports - All Applicants

Additional Reports – Only Combination Product Applicants

• Combination products, which are authorized under a NDA, ANDA or BLA, that include a device constituent part must also submit:

― Correction and removal reports (21 CFR 806.10), and keep related records (21 CFR 806.20)

― 5-day reports (21 CFR 803.3 and 803.53)

― Malfunction MDR reports, including follow-up (21 CFR 803.50 and 803.56),

See 21 CFR 4.102(c)

Additional Reports – Only Combination Product Applicants

• Combination products, which are authorized under a device application or BLA, that include a drug constituent part must also submit

― Field alert reports (21 CFR 314.81)

― 15-day reports (21 CFR 314.80)

― If the combination product is authorized for marketing as a device, this report may be submitted within 30 calendar days

rather than 15 calendar days

See 21 CFR 4.102(c)

Additional Reports – Only Combination Product Applicants

• Combination products, which are authorized under a device application, NDA or ANDA, that include a biological product constituent part must also submit

― Biological Product Deviation Reports (BPDR), (21 CFR 600.14 and 606.171)

― 15-day reports (21 CFR 600.80)

― If the combination product is authorized for marketing as a device, this report may be submitted within 30 calendar days rather than 15 calendar days

See 21 CFR 4.102(c)

When Can One Report Be Submitted?

• A combination product applicant may submit only one PMSR if the report

― Contains all of the information that would be required in another type of report,

― Is required to be submitted in the same manner under this rule as the other report, and

― Is submitted within the applicable deadlines

See 21 CFR 4.102

Periodic Safety Reports

• Combination product applicants whose product is authorized under an NDA, ANDA, or BLA must include in their periodic safety reports a summary and analysis of reports submitted under the requirements of this rule for constituent parts

― For combination products authorized under a device application, periodic safety reports are not required

See 21 CFR 4.102(d)

Information Sharing – Only Constituent Part Applicants

• Information sharing is required with other constituent part applicants for the combination product no later than 5 calendar days after receipt of the information, with recordkeeping. See 21 CFR 4.103

― Events that involve a death or serious injury, as described in 21 CFR 803.3 or an adverse experience, as described in 21 CFR 314.80(a) or 600.80

― Recordkeeping

― Copy of information provided to other constituent part applicants

― Date you received the information

― Date that you provided information to other applicants

― Name and address of each applicant to whom you provided the information

Maintaining Records

• Combination product applicant must maintain records

― For the longest time period required for any record under the PMSR regulations applicable to the authorization of your combination product (i.e., drug, device, biological product)

• Constituent part applicant must maintain records

― For the longest time period required for any record under the PMSR regulations applicable to the authorization of your constituent part (i.e., drug, device, biological product)

― This time period also applies to maintaining records of information that you shared with other constituent part applicants

See 21 CFR 4.105

Effective Dates of Compliance

• In general, January 19, 2017 (30 days after publication of the rule)

― Exceptions: May 20, 2018 (18 months after publication date)

― For combination product applicants, the additional reporting requirements for constituent parts in the rule at 4.102(c) and (d) and 4.104(b); also the recordkeeping requirements at 4.105(b)

― For constituent part applicants, the sharing information reporting requirements in the rule at 4.103 and recordkeeping requirements at 4.105(a)(2)

Combination Product Post Market Safety reporting (PMSR)

Application of the Final Rule

Khaudeja Bano Washington DC - June 8th 2017

Combination Products Regulation, Policy and Best Practices Postmarket Adverse Event Reporting and cGMP: What You Absolutely

Need to Know

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

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

Postmarket Adverse Event Reporting:

Case Scenarios

Beverly Lorell, MD Senior Medical & Policy Advisor FDA & Life Sciences Group King & Spalding

Case Scenario 3 Device-Drug Combination Product

Product – drug-eluting coronary stent

Application type – medical device (PMA)

• Stent is cobalt-chromium; permanent polymer is new formulation (1st time use in DES)

• Drug is an “olimus,”used in earlier versions of this stent for over five years.

Example: Introduced to market four months ago in US. In the last 3 weeks, company “VesselSure” has received 6 reports of early in-stent thrombosis that occurred three – four weeks after implant. All patients were complying with dual anti-platelet drug therapy, consistent with IFU. All cases were associated with heart attack, with one death. In one case, catheter retrieval of thrombus showed clot plus microscopic shards of possible polymer.

• Serious injury or death: Yes

• Label/Expectedness: No

• Association: Relatedness/May have caused or contributed: Yes

• PMSR: (21 CFR 803) Yes – 30-day MDR. Or, is 5-day report needed??

― Drug 15-day report: Yes. But, may be submitted at 30 days because product is approved as device and 30-day MDR is being submitted.

― Periodic safety report: No.

Case Scenario 4 Cross Labeled Combination Product

Product: drug and device cross labeled for photosensitization therapy

• “GlowPhyrin for Injection,” - manufactured by PharmaBest. Drug (NDA). A photosensitizing drug, activated with laser at 630 nm wavelength, indicated for use with “GlimmerFiber” for palliation of specific GI and bronchial tumors.

• “GlimmerFiber” – manufactured by GlowCo. Device (PMA). Optical diffuser fiber for delivering laser energy and indicated for use with the photosensitizing drug “GlowPhyrin” for palliation of specific GI and bronchial tumors.

Example: Introduced ten years ago in U.S. In last four months, both companies received three reports of Stevens-Johnson syndrome requiring ICU. Each occurred 12 – 24 hours after the 1st or 2nd photosensitizing treatment. PharmaBest’s analysis indicates presence of an adulterant – not yet identified – in the pertinent lot of Glowphyrin.

• Serious injury or death: Yes

• Label/Expectedness: No

• Association: Relatedness/May have caused or contributed: Yes

• PMSR: PharmaBest. Drug. 5-day Field Alert Report (FAR) - Yes. Periodic Report – Yes. 5-day Sharing with constituent part applicant – Yes.

― GlowCo. 30-day MDR?