us food and drug administration: 10 gleason 051005

8/14/2019 US Food and Drug Administration: 10 Gleason 051005

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Food and Drug Administration and Drug Information Association Cross-Labeling Workshop

Kathryn L. GleasonOn behalf of AdvaMed

Bethesda, MDMay 10, 2005

Combination Products and Mutually Conforming Labeling:

LEGAL ISSUES



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OVERARCHING PRINCIPLES FORPROPOSING SOLUTIONS TOCROSS-LABELING ISSUES

Optimal flexibility needed to encourageinnovation and advancement of public health

Combination law includes framework for analyzingwhen cross-labeling is needed (21 C.F.R. §3.2(e)(3))

Combination law provides separate and distinctauthority from drug and device laws, and permitsflexibility -- “any agency resources … necessary”

to accomplish combination law objectives (Section503(g)(2) of the Act)

Flexibility is seen in Intercenter Agreementprinciples and precedents; this flexibility should bepreserved and expanded



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OVERARCHING PRINCIPLES FORPROPOSING SOLUTIONS TOCROSS-LABELING ISSUES

Fairness:Non-cooperating entity (Co. A) must be protectedagainst undue responsibility/liability

Co. A proprietary information must be preservedconsistent with rights offered by existing law

New regulatory paradigm not needed:Existing statutory authority provides sufficient

fundamental legal structureClarifications may be made within thisframework

All issues of safety and efficacy must beaddressed (risk-based principles to beapplied)



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QUESTION 1:REASONS MANUFACTURERS DO NOT COOPERATE: EXAMPLES

Protecting intellectualproperty/assets

Product liability

Customer relations concernsNon-related commercialdisputes (e.g., between Co. A

Cost/resources/expertise indealing with new regulatory andscience issues

New safety/use concerns thatcould adversely affect drugfranchise

Competing R&D and/orpartnership interests withrespect to drug

Intellectual property

Competing R&D and/orpartnership interests withrespect to drug deliverysystem

Fraud and abuse

Protecting/directing businessstrategies

FDA exposure (QSR,postmarket compliance, etc.)

Commercial ConcernsLegal/RegulatoryConcerns



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QUESTION 1:REASONS MANUFACTURERS DO NOT COOPERATE (cont’d)

Involvement of FDA at premarket stageNo statutory authority for FDA to requirecooperation, and new statutory/regulatory authority

not desiredFDA intervention (even to request cooperation) notdesirable, absent Co. B concurrence. If Co. Bconcurrence, should not be barrier to FDAintervention.

Incentives (e.g., user fee waivers/reductions) couldbe considered, but should not require legislativefixes

• Note: Reasons for non-cooperation often

cannot be fixed by regulatory solutions

FDA INVOLVEMENT IN ENCOURAGING COOPERATION



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QUESTION 1:REASONS MANUFACTURERS DO NOT COOPERATE (cont’d)

Postmarket involvement by FDA: Greater

authority to require more active involvementby Co. A Supplemental requirements (21 C.F.R. §314.70(b))

GMP requirements

Postmarket vigilance (notification to FDA of safety problems) (21 C.F.R. §§ 310.305,314.80)

Postmarket labeling changes (Section 201(n) of the Act; 21 C.F.R. § 201.128)

FDA INVOLVEMENT IN ENCOURAGING COOPERATION



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QUESTION 2: INFORMATION THAT MAY AND MAY NOT BE USED IN SUPPORT OF COMPANY B’s PREMARKET REVIEW

Information that may not be used:Any solution must protect data to which Co. B doesnot have a right to reference

Section 505(l) of the Act provides protection of Company A’s safety and effectiveness data throughdate of approval of first ANDA

Any 505(b)(2) debates (e.g., including questionsabout “inherent” reliance) should be resolved underdrug law -- not a combination law issue



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QUESTION 2: INFORMATION THAT MAY AND MAY NOT BE USED IN SUPPORT OF COMPANY B’s PREMARKET REVIEW (cont’d)

Information that may be relied on:

Both drug and device laws permit use of information inpublic domain to support approvals (e.g., 505(b)(2) process;

21 C.F.R. §§ 814.9(f)-(h), 814.20(b)(8), 20.81))Drug laws recognize that changes in dosage, route of administration, and indication could be supported by publicdomain information (FDA, Applications Covered by Section505(b)(2) (Draft, Oct. 1999))

Combination policies historically have acknowledged thatprior approvals may reduce efficacy data demands forcombined drug/device products

• CDER/CDRH ICA: “an additional showing of clinicaleffectiveness of the drug when delivered by thespecific device will generally not be required”



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QUESTION 3: ENSURING ADEQUACY OF COMPANY LABELING

Adequacy of Labeling from Regulatory Perspective

Law allows for differentiating adequacy of druglabel from labels of those products subject tocombination law

Section 503(g)(2): “[n]othing shall prevent us[e][of] any agency resources … necessary to ensureadequate review of the safety, effectiveness, orsubstantial equivalence of an article”

Questions Co. A will ask with respect to theregulatory adequacy of its labeling:Sections 201(n), 502 of the Act; 21 C.F.R. §201.128 -- Does awareness of new use imputeobligation to revise labeling?

Supplemental laws (Section 505 of the Act, 21C.F.R. 314.70 -- Does awareness of new use



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QUESTION 3: ENSURING ADEQUACY OF COMPANY LABELING

Adequacy of Labeling from Regulatory Perspective (cont’d)

FDA clarifications will be required to protect Co. Afrom needless regulatory exposure

FDA should more expressly acknowledge thatcombination law represents a unique regulatorycategory, and that combination law can bedefined separately from drug and device laws(Sections 503(g), 563 of the Act)

FDA could stipulate that Company B will be solelyresponsible for premarket review of labelingadequacy (including adequate directions for use)FDA could stipulate that approval/clearance of Co.B’s labeling would not itself cause misbranding of Co. A’s product

FDA may wish to retain some postmarketmisbranding authority, if, for example, Co. A



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QUESTION 3: ENSURING ADEQUACY OF COMPANY LABELING (cont’d) Adequacy of Labeling From a Commercial(e.g. , Product Liability) Perspective

Where product is “individually specified”(branded, proprietary) in labeling

Concerns with adequacy of warnings and relatedtheories, since Co. A will be aware of new usesCo. A concerns with confusion/conflicts created byCo. B labelingProtections that FDA offers to mitigate theseconcerns

• Possible preemption if reviewed underdevice law; theories untested

Ordinary course of business: contractualagreements need to define roles/responsibilities of parties to address these liability concerns



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Where product is not “individually specified”(i.e., not branded, proprietary) in labeling:

Co. A product will not be cited specifically in Co. Blabeling

Thus, Co. A liability should not be a significant

concernAll clinically relevant information on use of devicewith drug will be included in device labeling

QUESTION 3: ENSURING ADEQUACY OF COMPANY LABELING (cont’d)

Adequacy of Labeling From a Commercial(e.g. , Product Liability) Perspective



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QUESTION 4: EXCLUSIVITY IMPLICATIONS

Principal purposes of FDA exclusivity laws:protection against inappropriate generic drug competition and inappropriate use of proprietary dataAssuming no reliance on proprietary drug dataand no generic drug competition , drugmarketing exclusivity should not impede device

(PMA/510(k)) review of Co. B productIf patent issues, Co. A and Co. B would addressthose issues through appropriate (non-FDA)legal recourse

Even with these safeguards, AdvaMed

nonetheless believes that contractuala reements between Co. A and Co. B will be



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QUESTION 4: USE OF GENERICS OROTHER “PUBLIC DOMAIN” DRUGS(e.g. , USP) (cont’d)

Drugs for which non-proprietary information may beavailable:

ANDA drugs; drugs otherwise off-patent and

without market exclusivity; USP, grandfathered,DESI, and OTC drugs

Existing law recognizes that these drugs should notrequire mutual conformance in Co. A labeling

These drugs would not be “individually specified”(i.e., by brand) in Co. B labeling21 C.F.R. § 3.2(e)(3) affords optimal flexibilitywhere drugs are not individually specified; cross-labeling not required

Change management less of an issue; existing laws forthese drug categories do not allow for significant



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QUESTION 5: REGULATORY TOOLSTO ENSURE APPROPRIATE ONGOINGFDA OVERSIGHT

Co. B conditions of approval; special controls for510(k) devices

21 C.F.R. §§ 814.44(e), 814.82Section 513(a)(1)(B) of the Act

Co. A and Co. B notification to FDA of drugspecifications/manufacture changes, as

requiredSections 505, 506A of the Act; 21 C.F.R. §§ 314.70(b), 807.81(a)(3),814.39

Co. A and Co. B GMPs/QSRsSections 501(a),(h), 520(f) of the Act; 21 C.F.R. Parts 211 and 820



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QUESTION 5: REGULATORY TOOLSTO ENSURE APPROPRIATE ONGOINGFDA OVERSIGHT (cont’d)

Co. A and Co. B postmarket reportingmechanisms

E.g., Section 519 of the Act; 21 C.F.R. §§ 310.305, 314.80,Part 803

Authority of FDA to require changes to Co. Aand Co. B labeling as needed

Section 201(n) of the Act; 21 C.F.R. §§ 201.128, 801.4Conclusion: FDA has ample oversightauthority over Co. A and Co. B products usedtogether



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QUESTION 6: OPTIMAL APPROACHFOR CLARIFYING RELEVANT LAW

Clarifications needed; ideally accomplishedthrough guidance

Examples of clarifications needed to encourageinnovation and allow Co. B to proceed

Cross-labeling standards should be applied withoptimal flexibility to allow efficient, cost-effectivedevelopment of innovative products

Terms of “cross-labeling,” “mutual conformance,”and “individually specified” should be defined

Device labeling alone may address drug used withdevice, where the drug is not “individuallyspecified” (i.e., branded, proprietary)



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QUESTION 6: OPTIMAL APPROACHFOR CLARIFYING RELEVANT LAW (cont’d)

Examples of clarifications needed to encourageinnovation and allow Co. B to proceed (cont’d)

Combination law is distinct from device and druglaw and permits flexible solution: “any agencyresources … necessary” to accomplish regulatoryobjectives (Section 503(g)(2) of the Act)

Drugs for which historical safety and effectivenessinformation is available in the public domain, shouldnot be considered “individually specified”Further clarification of information that may berelied on in the public domain, to support reviews(see slide 8)

Clarification that ICA principles of flexibility will besustained and expanded



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QUESTION 6: OPTIMAL APPROACHFOR CLARIFYING RELEVANT LAW (cont’d)

Examples of clarifications needed to protectCo. A

Affirmation that Co. A’s proprietary information isto be protected consistent with current law

Clarifications needed to protect Co. A from undueresponsibility/liability

•E.g., clarification that Co. B alone isresponsible for premarket reviewconcerning adequacy of labeling, testing,and design of delivery system/drug

Enumeration/affirmation of postmarket

regulatory oversight tools



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QUESTION 7: OTHER LEGALCONSIDERATIONS

Roles of/relationship between Co. A and Co. B onsuch issues as: respective responsibilities with

regard to inspections; promotion; recalls; andother compliance activities relating to labelingScenario 1 (branded, proprietary drug) --Roles/responsibilities to be determined by contractualagreement

Scenario 2 (drug is not “individually specified”) -- Co. Bwould be principal point of contact with FDA

Other legal issues addressed during public healthdiscussion (e.g., degree of labeling conformancerequired)



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Food and Drug Administration and Drug Information Association Cross-Labeling Workshop

Kathryn L. GleasonOn behalf of AdvaMed

Bethesda, MDMay 10, 2005

Combination Products and Mutually Conforming Labeling:

LEGAL ISSUES

us food and drug administration: 10 gleason 051005

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