6. Combination Products Original Trends - (Scott Sardeson)

SAVE OFFLINE

Combination Products: Original Trends / Productos Combinados: Tendencias Scott Sardeson RAC (EU/US) International Regulatory Affairs and Quality Compliance Director 3M Health Care Business April 2016, Santiago Chile

1

Comparison of Regulatory Models In 2007, The former Global Harmonization Task Force (GHTF) Established Ad Hoc Working Group to study their regulatory models •

Reviewed existing GHTF documents to see what changes needed

•

Established a working harmonized definition

•

Developed general principles for regulation of combination products

•

Considered establishing liaison with appropriate medicines and biological organizations

2

Combination Product Definition Definition of Combination Products AUS

Not defined as a separate product. Combination products regulated according to main function/purpose of the combination product.

Canada

A therapeutic product that combines a drug component and a device component (which by themselves would be classified as a drug or a device), such that the distinctive nature of the drug component and device component is integrated in a singular product.

Japan

No specific definition. Combination products are regulated according to main function/purpose of the combination product.

US

Product comprised of 2 or more regulated components that are physically, chemically or otherwise combined or mixed and produced as a single entity or co-package product, or as cross-labeled products.

EU

No general definition of combination product. A ‘combined advanced therapy product’ is defined as one that incorporates as an integral part one or more medical devices, or active implantable medical devices, and viable cells or tissues, or non-viable cells or tissues where the action on the human body of these cells or tissues is primary to the device. 3

Combination Product Reviews Agency Review Determinations – Who is the lead? AUS

Consider primary intended purpose and mode of action. May be referred to an internal committee consisting of staff from relevant regulatory areas of TGA.

Canada

Medical Devices Bureau – when classified as a Device.

Japan

PMDA leads review – Offices under PMDA will lead depending on how the CP is regarded.

US

Assignment by Office of CP to Agency Center based on “primary mode of action” of CP. If PMOA cannot otherwise be determined, assignment will be based on the following algorithm: If there is an Agency Center that regulates other CPs presenting similar questions of safety & efficacy with regard to the CP as a whole then the CP should be assigned to that Agency Center. If not, the CP will be assigned to the Agency Center that has the most expertise related to the most significant safety & efficacy question presented by the combination product.

EU

Consider primary mode of action. Opinions must be sought from relevant expert committees for certain CPs. 4

Quality System Requirements GMPS/QS Requirements AUS

Same as for other Medical Devices or Medicines.

Canada

Required to meet acceptable standards of safety, efficacy and quality.

Japan

According to main function (drug, device) requirements.

US

Draft guidance published 2004. Proposed regulation is under development.

EU

Same as for other Medical Devices or Medicinal Products.

Adverse Event/Vigilance Reporting Requirements AUS

Same as for other Medical Devices or Medicines.

Canada

Same as for other Medical Devices or Medicines.

Japan

According to main function (drug, device) requirements.

US

Draft concept paper published 2004. Proposed regulation is under development.

EU

Same as for other Medical Devices or Medicinal Products. 5

Global Comparison – Combination Product Regulations Convergence but challenging Most countries do not have clear paths to regulated medical products Three models, Regulate based on : 1. Highest risk constituent part – contains a medicine therefore a drug 2. Most apparent use – looks like a wound dressing so must be a device 3. Primary mode of action – Intended use a wound dressing

It is globally difficult to manage if regulations are not harmonized • Regulatory requirements do not match – container closure for a device? design controls for a pharmaceutical? • Certificate of Pharmaceutical Product versus Certificate of Free Sale 6

How are Such Complicated Product Regulated Some issues that arise in regulating combination products are the following: Diverse kinds of products Different jurisdictions in regulating Agencies Interactions between the combined regulated products Quality System Requirements (Drug GMP or Device QMS)

7

s

US FDA Approach to Combination Products

8

Combination Product in the United States - Definition Combinations of drugs, devices, and/or biological products (not combinations of same type, e.g., drug with a drug) Types include: • Chemically or physically combined products (e.g., drug-eluting stents, patches, or implants; prefilled autoinjectors or syringes, metered dose inhalers) • Co-packaged products (e.g., first-aid kits; surgical kits) • “Cross-labeled” products (e.g., photosensitizing drug and activating light source labeled specifically for use with one another)

Legal nature = that of the constituent parts “plus.” There are no U.S. statutory or regulatory standards specifically for combination product 9

Combination Product Concepts US FDA has three key concepts it uses in the regulation of combination products 1.

Constituent parts retain regulatory status and duties

2.

Combination products are a distinct regulatory class

3.

Comprehensive, effective oversight without undue redundancy

10

US FDA General Goals & Considerations US FDA has some general goals and considerations in the regulation of combination product • Consistency, coordination, clarity • Agency SOPs, training, guidance, information technology • Value of an independent coordinating body between Centers • Building upon existing systems v. creating a new one • Submissions (NDA, PMA, 510K, IDE) • Quality Systems and GMP • Adverse Event Reporting

Very helpful to industry also in order to assure predictability

11

US FDA General Considerations & Factors These require establishing • Sound, consistent review standards • Appropriate expertise • Timely review • OCP duty to ensure timely effective premarket regulation • Statutory authority to use all agency resources

12

Who Regulates? In US the lead center is defined by the Primary Mode of Action (PMOA) The lead center assignment can be from one of the following: • Center for Drug Evaluation and Research (CDER) • Center for Devices and Radiological Health (CDRH) • Center for Biologics Evaluation and Research (CBER)

Example: • Drug eluting stent or wound dressing with antimicrobial – typically a device (CDRH) • Asthma inhaler or medicinal patch – typical a drug (CDER)

13

Application Process • Lead Center Assignment – Who will be primary Center for the product? • Investigational Application - Is it necessary and if so what is required? • Marketing Application - What path will be used for product clearance or approval? • Coordination – How will the US FDA manage the information internally?

14

Product Characteristics are Important Factor The US FDA considers the following characteristics to determine requirements • What is new or different, e.g., • Inclusion of drug that is a new molecular entity • New indication, area of use/exposure • Different drug formulation or device modification • Change in dosing • Complexity or new science/technology • New population, new risks

15

Marketing Application Once submitted the product application has a coordinated review by Centers • Generally only one marketing application needed • If two are appropriate (may be the case for cross-labeled combination products), authorize marketing only when/if both are ready for approval/clearance Facility inspections by staff is conducted with appropriate expertise for all constituent parts • Strong business relationships can be essential, e.g., to ensure success • Ongoing reliance on proprietary data • Appropriate coordination of post marketing changes to constituent parts

16

Q. System Requirements Co-packaged or single-entity combination product

If the combination product includes a device constituent part and a drug constituent part, and the current good manufacturing practice operating system has been shown to comply with the drug cGMPs, the following provisions of the QS regulation must also be shown to have been satisfied:

21 CFR 820.20. Management responsibility. 21 CFR 820.30. Design controls. 21 CFR 820.50. Purchasing controls. 21 CFR 820.100. Corrective and preventive action. 21 CFR 820.170 Installation and/or 21 CFR 820.200 Servicing, where the combination product or constituent part would have hardware requiring such installation and/or servicing.*** ***This was not identified in the 2004 Combination Product GMP Draft Guidance document but current thinking is that this may be necessary

17

Q. System Requirements Co-packaged or single-entity combination product

If the combination product includes a device constituent part and a drug constituent part, and the current good manufacturing practice operating system has been shown to comply with the QS regulation, the following provisions of the drug cGMPs must also be shown to have been satisfied:

21 CFR 211.84. Testing and approval or rejection of components, drug product containers, and closures. 21 CFR 211.103. Calculation of yield. 21 CFR 211.137. Expiration dating. 21 CFR 211.132. Tamper-evident packaging requirements for over-the-counter (OTC) human drug products. 21 CFR 211.165. Testing and release for distribution. 21 CFR 211.166. Stability testing. 21 CFR 211.167. Special testing requirements. 21 CFR 211.170. Reserve samples.

18

US FDA Office of Combination Products (OCP) The role of the Office is as follows: • Classifies and assigns products for regulation • Coordinates and oversees regulation of combination products • Resource for industry

Develop SOP’s for inter-center consultation with Centers:

The Office of Combination Products (OCP) is a statutorily mandated office

• Consults same priority as assigned products • Consultation/collaboration as needed

Sponsors and review staff Consultations • Facilitate meetings • Resolve product class and product specific combination product concerns • Resolve disputes between Centers or with sponsors 19

Policy & Practice Development OCP works with CBER, CDER, CDRH, and other agency components as appropriate to establish and clarify regulatory approaches and pathways • Inter-center coordination in the US FDA • Reviewer tools and training • Inter-center working groups • Internal memoranda of understanding and standard operating procedures • Guidance and regulations of combination products

20

US FDA Observations Some of the lessons the US FDA has learned are • Coordination and application of consistent, appropriate, review standards is important • Systemic drivers and establishing new procedures and duties for combination products • Evolving process and guideposts • Value of independent coordinating body

21

s

European Approach

22

European Approach The Medical Device Directive classifies any medical device with a ancillary medicinal substance as a Class III medical device. 1. The CE Mark is obtained by submitting a design dossier to a EU Notified Body (NB) 2. The NB will do a consult with a EU Competent Authority on the drug aspects 3. CE Mark approval is granted by the NB 4. The product is subject to Quality System Requirements (ISO 13485) and AE reporting as a medical device

23

s

Thank You Scott Sardeson RAC (EU/US) 3M Health Care Business St. Paul, MN USA [email protected] 24