James S. Cohen, Esq . McDermott Will & Emery LLP 202.756.8276 jscohen@mwe March 31, 2011

1. AdvaMed Medical Technology Learning Institute – Proposed Rule, cGMP for Combination Products: Framework, Impact, and Issues James S. Cohen, Esq. McDermott Will & Emery LLP 202.756.8276 jscohen@mwe.com March 31, 2011

2. Overview • General Principles • Legal & Regulatory Framework • Impact • Alternative Approaches • Issues/Concerns • Take Home www.mwe.com

3. Combination Products • Combinations of different types of products: • Drug-device; device-biologic; drug-biologic; drug-device-biologic • NOT drug-drug, device-device, or biologic-biologic • They can be: • Physically or chemically combined • Co-packaged in a kit • Separately packaged; Cross-labeled www.mwe.com

4. Purpose • To clarify when, and which, cGMP requirements apply when drugs, devices, and biological products are combined “to create” a combination product (CP) • To set forth “transparent and streamlined” framework for manufacturer to demonstrate compliance with cGMP requirements for “single-entity” and “co-packaged” CP www.mwe.com

5. Background • FDA responsible for ensuring “consistent and appropriate” postmarket regulation of combination products • Medical Device User Fee and Modernization Act of 2002; 21 U.S.C. 503(g) • There are now no independent regulations on current good manufacturing practice (cGMP) for combination products (CP’s) • This is a significant absence www.mwe.com

6. Underlying Legal Principle • FDA’s legal/regulatory position: • Each “constituent part” of a CP is a drug, a device, or a biological product independently subject to cGMP regulation under the FDCA → Each “distinguished by its [independent] regulatory identity” • The CP also has an independent identity and is subject to cGMP regulation www.mwe.com

7. Framework • Draft Guidance 9/24/04 • Each constituent part (drug, device, and/or biological product) is subject to its underlying set of cGMP regulations • Includes human cell, tissue, or cellular or tissue-based products (HCT/P’s) regulated as a drug, device, or biological product www.mwe.com

8. Framework • Draft Guidance:“during and after” combination, both sets of regulations (for constituent parts) apply • PR: When constituent parts arrive at, are manufactured in, or are combined to create a CP in same facility, both sets apply • PR applies to single-entity and co-packaged CP’s www.mwe.com

9. Framework • PR recognizes: • Many facilities operate under one manufacturing system • cGMP (drug) & QS (device) regulations similar • Each regulation contains key elements based on “unique characteristics”for which each was designed www.mwe.com

10. Framework • Underlying regulatory principle: • Compliance with both sets of regulations (for the constituent parts) can generally be achieved: → By using either regulation → As long demonstrate compliance with key provisions from other set • Identifies provisions of each set that: • Differ in specificity, and must be followed if operate under one “umbrella”system www.mwe.com

11. Framework ■ A properly designed/implemented system under one set of regulations will in most instances meet requirements of other set ■ To allow flexibility to select cGMP or QS Regulation as “umbrella” system, but only if can demonstrate compliance with specified provisions from other set ■ CP’s would be subject to similar requirements regardless of lead Center or application type ■Avoid need for parallel operating systems www.mwe.com

12. Two Options for Manufacturer • Two options: • Demonstrate compliance with both sets of underlying cGMP regulations (i.e., cGMP and QS Regulation), or • Demonstrate compliance with “umbrella” system under one set of underlying cGMP regulations that incorporates required provisions from other set of regulations www.mwe.com

13. “Umbrella” System • PR identifies the specific provisions of the “other set of regulations” (e.g., cGMP and QS Regulations) for which a manufacturer must demonstrate compliance when operating under an “umbrella” system www.mwe.com

14. Required Provisions • If operating under a cGMP regulation system: • Manufacturing controls (21 CFR 820.20) • Design controls (820.30) • Purchasing controls (820.50) • Corrective and Preventive Action (CAPA) (820.100) • Installation (820.170 • Servicing (820.200) www.mwe.com

15. Required Provisions ■If operating under a cGMP regulation system, cont.: • If CP includes a biological product constituent part, then blood and blood product (21 CFR Part 606), and biological product standards (21 CFR Parts 600-680 • If CP includes a HCT/P constituent part (regulated as a drug, device, or biological product), Current Good Tissue Practice (cGTP) and donor eligibility requirements of 21 CFR Part 1271 www.mwe.com

16. “Umbrella” System • If operating under a QS Regulation system: • Testing & approval/rejection of components, drug product containers, and closures (21 CFR 211.84) • Calculation of yield (211.103) • Tamper-evident packaging for OTC human drug products (211.132) • Expiration dating (211.137) • Testing and release for distribution (211.165) • Stability testing (211.166) • Special testing requirements (211.167) • Reserve samples (211.170) www.mwe.com

17. Required Provisions ■If operating under a QS Regulation system, cont.: • If includes a biological product constituent part, blood and blood product (21 CFR Part 606), and biological product standards (21 CFR Parts 600-680 • If includes a HCT/P constituent part (regulated as a drug, device, or biological product), Current Good Tissue Practice (cGTP) and donor eligibility requirements of 21 CFR Part 1271 www.mwe.com

18. Comparison to Draft Guidance • PR adds (1) management responsibility, (2) installation, and (3) servicing from QS Regulation to the required provisions if under cGMP “umbrella” system • PR sets forth all required additional provisions from other set • whereas Draft Guidance states other additional provisions may apply (as determined by manufacturer or FDA) depending upon the particular CP www.mwe.com

19. Impact of Prospective Regulation • Would be the most significant CP rulemaking since PMOA rule in 2005 • Because there are no current cGMP regulations for CP’s, and because of FDA’s significantly enhanced focus on product safety and enforcement, rule will be a major regulatory action with substantial impact on CP innovation and development www.mwe.com

20. Alternatives • There are a number of ways in which FDA could seek to regulate cGMP for CP’s. These include: • Maintain status quo, with only the current underlying regulations for each constituent part. Some would argue: → Not viable, realistic, or consistent with FDA’s statutory mandate, particularly as more innovative and complex CP’s are now being developed and marketed → Could lead to inconsistent postmarket regulation of similar or “like” products www.mwe.com

21. Alternatives • Expressly require by regulation that each set of underlying regulations apply in all instances → Many would view this as impractical, burdensome, costly, and that it would inhibit innovation/improved health care • Provide that PMOA and/or marketing application determine which set applies → Pros: some believe this is the most clear, consistent, and least burdensome approach → Cons: some argue it would not account for the unique characteristics, or particular safety concerns, for the underlying (secondary) constituent part(s) www.mwe.com

22. Alternatives • PR approach → Umbrella, plus required additional provisions ▪ Pros: many believe this is the most realistic and flexible under the current statutory framework for CPs ▪ Cons: still lacks predictability, would impose a demonstration burden on manufacturers, and could often lead to inconsistent enforcement www.mwe.com

23. Outstanding Issues/Concerns • Proposed Rule published 19 months ago • no interim guidance has issued • What are key issues and concerns for industry? They include: • What is the legal basis to support the application of each underlying cGMP regulation to each constituent part and to the finished CP? • When is a constituent part considered a finished component? www.mwe.com

24. Outstanding Issues/Concerns • Must it be a finished component? (see 21 C.F.R. 210/211, 820) – As the legal basis for the application of both sets of regulations to all constituent parts and to finished product, preamble relies generally on: → Adulteration provisions of section 501 of FDCA → General authority to issue regulations in section 701(a) of FDCA → General authority to designate CP product jurisdiction, and ensure consistent and appropriate CP postmarket regulation, of CP’s in Section 503(g) of FDCA www.mwe.com

25. Outstanding Issues/Concerns • PR further defines “during and after” of Draft Guidance to describe at which point both sets apply – When two or more constituent parts that are to be included in a CP arrive at, or are manufactured at, same facility – Has been primary concern for industry – Should also be in a codified definition www.mwe.com

26. Outstanding Issues/Concerns • What is the “flexibility” under “umbrella” system? – The regulation would list (codify) all required provisions from “other" set of regulations that must be incorporated →Except biological product and HCT/P regulations may also apply – Unlike Draft Guidance, PR does not require that additional provisions from the other set “may also be necessary, as determined by manufacturer or FDA” www.mwe.com

27. Outstanding Issues/Concerns → But, can still be held accountable for underlying set of cGMP regulations for each constituent part → Does not allow manufacturer to request alternatives to a cGMP requirement (as in other regulations) ▪ This should be added to final rule ■Biological product requirements and “standards” in Parts 600-680 – PR does not explain which “requirements” of 600-680 apply, or how to apply these provisions to the CP or codified scheme (same issue applies for HCT/P’s) – Preamble notes some provisions of 600-680 are not “requirements,” but PR does not further describe or explain www.mwe.com

28. Outstanding Issues/Concerns ■ Preamble recognizes need for “timely comprehensive guidance and training,” but FDA does not plan to issue guidance until after final rule implemented ■How does/will FDA ensure that its inspections and compliance/enforcement activities are “consistent and appropriate” during PR period (i.e., now)? – How do/will (a) field investigators and (b) ORA and Center compliance officers regulate manufacturing during period between proposed and final rule? → Little guidance available www.mwe.com

29. Outstanding Issues/Concerns ■ What is/will be the training for FDA investigators/compliance officers in absence of Compliance Policy Guide? – Are they/will they be advised to perform inspections/compliance oversight based on the guidance of PR preamble? – More broadly, how does/will FDA ensure Center review/safety/compliance offices communicate and share information with each other? → particularly before FDA’s IT system is updated Will the regulation apply to products on the market (legacy products) ■ Post-approval changes (“change control”) → Which set of regulations to follow www.mwe.com

30. Outstanding Issues/Concerns ■How can manufacturers learn what types of compliance actions FDA has taken for CP’s? – Not currently independently tracked; few Warning Letters issued/published ■ Will FDA track and publish compliance activity/actions relating to CP’s as it does for other products? ■ Which is FDA’s “current thinking,” PR or earlier Draft Guidance (which remains available on FDA website)? ■ Need to explain the application of the statutory definition of “chemical action” to drug vs. device jurisdictional determinations – Impacts which system to use under “umbrella” system www.mwe.com

31. Take Home Considerations • Very important to know that, under FDA’s proposed scheme, CP manufacturer could still be citedfor violation ofthe underlying set(s) of cGMP regulationsfor eachconstituent part (i.e., each set of regulations) • Under the proposed regulation, the burden is on manufacturer to demonstrate compliance with regulatory scheme www.mwe.com

32. Take Home Considerations • If use “umbrella” system, plan how you will address and demonstrate compliance with: – Required provisions from secondary set(s) of regulations • During pre-application period, generally helpful to request meeting with both Centers present to reach agreement on your “umbrella” system, especially during period between proposed and final rule – Confirm in writing – Present to investigators at beginning of inspection www.mwe.com

33. Take Home Considerations • Final rule will significantly affect all manufacturers • Major step forward, which will be welcomed by many in industry • But, the final regulation must not create burdens or inhibit CP product innovation and development • FDA transparency between PR/final rule is essential – particularly given FDA policy of limited public information on PMOA and product jurisdiction decisions www.mwe.com

34. Take Home Considerations • Every CP developer/manufacturer should examine PR and how final rule will affect its development plans/manufacturing operations • If you have any concerns or questions about the application of the scheme to your products, particularly during the period of uncertainty between the proposed and final rule • contact counsel or OCP or Office of Compliance of appropriate Center www.mwe.com

35. Thank You • Please feel free to contact me should you have any questions • jscohen@mwe.com • 202.756.8276 (office) • 301.312.9808 (mobile) • http://www.mwe.com/fda/ www.mwe.com