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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 [email protected] March 31, 2011 www.mwe.com Boston Brussels Chicago Düsseldorf Houston London Los Angeles Miami Milan Munich New York Orange County Rome San Diego Silicon Valley Washington, D.C. Strategic alliance with MWE China Law Offices (Shanghai) © 2010 McDermott Will & Emery LLP. McDermott operates its practice through separate legal entities in each of the countries where it has offices. This communication may be considered attorney advertising. Previous results are not a guarantee of future outcome. The following legal entities are collectively referred to as "McDermott Will & Emery," "McDermott" or "the Firm": McDermott Will & Emery LLP, McDermott Will & Emery/Stanbrook LLP, McDermott Will & Emery Rechtsanwälte Steuerberater LLP, MWE Steuerberatungsgesellschaft mbH, McDermott Will & Emery Studio Legale Associato and McDermott Will & Emery UK LLP. These entities coordinate their activities through service agreements. This communication may be considered advertising under the rules regulating the legal profession. Overview General Principles Legal & Regulatory Framework Impact Alternative Approaches Issues/Concerns Take Home www.mwe.com 2 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 3 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 4 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 5 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 6 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 7 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 8 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 9 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 10 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 www.mwe.com need for parallel operating systems 11 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 12 “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 13 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 14 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 15 “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 16 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 17 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 18 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 19 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 20 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 21 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 22 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 23 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 24 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 25 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 26 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 27 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 28 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 29 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 30 Take Home Considerations Very important to know that, under FDA’s proposed scheme, CP manufacturer could still be cited for violation of the underlying set(s) of cGMP regulations for each constituent 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 31 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 32 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 33 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 34 Thank You Please feel free to contact me should you have any questions [email protected] 202.756.8276 (office) 301.312.9808 (mobile) http://www.mwe.com/fda/ www.mwe.com 35