fda’s proposed generic labeling€¦ · fda’s proposed generic drug labeling rule – the...


FDA’s Proposed Generic Drug

Labeling Rule – the Backdrop

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Labeling Rule – the Backdrop

• Many in industry anticipated an FDA regulatory

change in response to Mensing

• Supreme Court affirmed that the Hatch-Waxman Act

prevents generic manufacturers from altering their

labels unilaterally and preempts state tort claims for

failing to do so

• In Bartlett, DOJ’s amicus brief alluded to a change

in regulatory course by FDA

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Labeling Rule – the Backdrop (cont’d.)

• On November 13, 2013, FDA published a proposed

rule “Supplemental Applications Proposing Labeling

Changes for Approved Drugs and Biological

Products” in the Federal Register

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• Intended to create parity between ANDA and NDA

holders

• Response to Mensing, to alter incentives for generic

companies to comply with post-marketing surveillance,

evaluation and reporting so that labels are timely

updated, accurate and complete

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• Comment period closed March 2014;

• Over 115 comments were received

• Lawmakers questioned the Proposed Rule, e.g.,

January 22, 2014 letter from Congress to

Commissioner Hamburg expressing “grave

concerns” over the proposed regulations

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Labeling Rule – The Details



Labeling Rule – The Details

• Traditionally, ANDA holders use Changes Being Effected-0 days (“CBE-0”) supplements only to make label changes already made by the RLD holder or to respond to an FDA request for a label change, not for unilateral label changes initiated by the generic company

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Labeling Rule – The Details (cont’d.)

• Under the Proposed Rule, when an ANDA holder has safety-related “newly acquired information,” the ANDA holder can use a CBE-0 supplement to unilaterally seek a label change

• ANDA holders can propose product labeling revisions

• ANDA holders are required to conduct surveillance,

evaluation and reporting of post-marketing adverse

events

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• ANDA holders can send “Dear Healthcare

Provider”/“Dear Doctor” letters regarding the CBE-0

supplement label change

• Labeling regulations at 21 C.F.R. are to be amended to

reflect these changes

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• An ANDA or NDA holder must submit a CBE-0

supplement if newly acquired information would

achieve any of the objectives in §314.70(c)(6)(iii)(A)

through §314.70(c)(6)(iii)(D):

• To add or strengthen a contradiction, warning,

precaution, or adverse reaction

• To add or strengthen a statement about drug abuse,

dependence, or dosage

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• To add or strengthen an instruction about dosage and

administration that is intended to increase the safe use

of the product; or

• To delete false, misleading, or unsupported indications

for use or claims of effectiveness

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• CBE-0 supplement should also include the source

of the data for the label change and the basis for

the change

• CBE-0 supplement can also be used to change the

“Highlights” information of the label, which

summarizes the most important safety and health

information in the label

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• Distribution of amended labels

• After an ANDA holder submits a CBE-0 supplement to

FDA, the ANDA holder can implement the label change

and distribute prior to FDA approval of the CBE-0

supplement (as is currently permitted for NDA holders

using CBE-0 supplements for label changes)

• The ANDA holder can use all available means to

distribute the revised label, e.g., healthcare provider

letters

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• Notification

• ANDA holders must notify the NDA holder of the

proposed label change (where the NDA has not been

withdrawn) and send a copy of the supporting

information at the same time the CBE-0 supplement is

sent to FDA

• ANDA holder must provide FDA with confirmation of the

notice to the NDA holder

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• NDA Holder Responsibilities

• As part of its responsibilities to review and evaluate

post-marketing data, an NDA holder must:

• Review the label change

• FDA notes that it would benefit from the views of the

NDA holder based on its review of the post-marketing

data, though timing of the NDA holder’s input is not

provided

• Submit the label change itself via CBE-0 supplement

or choose not to make the submission 16




• FDA may request that the NDA holder submit a

labeling change if appropriate

• NDA holder retains responsibility to update its label even

if it has discontinued marketing the product (exception

for withdrawn products)

• NDA holder is also responsible for distributing

information about its label change

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• Implications for other ANDA or NDA holders

• FDA may request label changes from other ANDA

holders as well as NDA holders/ANDA holders of related

products

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Creation of FDA Webpage


Creation of FDA Webpage

• FDA will create a dedicated webpage for publishing

the CBE-0 supplements

• ANDA holder must verify that the correct information

appears on the webpage or notify FDA if the

information is incorrect, within 5 business days of

posting

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Creation of FDA Webpage (cont’d.)

• NDA and ANDA holders can monitor webpage

• Submit their own CBE-0 supplements; or

• Provide comments to FDA about a pending CBE-0

supplement

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Creation of FDA Webpage (cont’d.)

• The webpage will contain CBE-0 supplements that

are submitted by different sponsors for a single drug

product – this information could potentially conflict

and cause confusion to healthcare providers and

patients

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FDA Evaluation of CBE-0

Supplements


FDA Evaluation of CBE-0 Supplement

• As a preliminary matter, FDA will review the change

proposed in a CBE-0 supplement to ensure that it is

properly a CBE-0 supplement and not a prior

approval supplement (PAS), which requires prior

FDA approval before the proposed change can be

distributed • If the proposed change should have been submitted via

PAS, FDA will convert the CBE-0 to a PAS and the

manufacturer must stop distributing revised labeling and

revert back to the original labeling until FDA approves

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FDA Evaluation of CBE-0 Supplement (cont’d.)

• FDA will then review the CBE-0 supplement and

• Approve the supplement, resulting in the same labeling

for the RLD and other generics, or

• Not approve the CBE-0 supplement and issue a

complete response letter

• No timeline is specified for FDA review of the CBE-0

supplement

• Likely to take a long time; multiple proposed changes

based on different data

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FDA Evaluation of CBE-0 Supplement (cont’d.)

• After FDA approves the label change for the NDA-

holder, ANDA holders have 30 days to submit a

CBE-0 supplement with the conforming label

change and

• Promptly distribute revised labeling

• Timely distribute product with the updated labeling

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Potential New Obligations for

ANDA and NDA holders


Potential New Obligations for ANDA

and NDA holders

• Obligation on ANDA holder to conduct surveillance,

evaluation and reporting of post-marketing adverse

events

• Burden on ANDA holders to propose new labeling

changes based on new information

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and NDA holders (cont’d.)

• Burden on NDA holder to review new information

from potentially a number of ANDA holders for any

one product

• Burden on all application holders to monitor FDA’s

webpage for CBE-0 supplements and decide how to

respond (agreeing with change or responding to

proposal)

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and NDA holders (cont’d.)

• No timelines established for

• How quickly an ANDA holder needs to update its

labeling as appropriate in view of new information; or

• How quickly the NDA holder needs to review the ANDA

holder’s information or proposed changes

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Comments on the Proposed Rule


Comments on the Proposed Rule

• Some support for improved generic labeling, more

equal responsibility for labeling changes between

NDA and ANDA holders, and timely updating of

generic labels

• But most view the Proposed Rule as radical

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Comments on the Proposed Rule (cont’d.)

• Criticism on a variety of fronts: increased and new

obligations, potential liability, costs and burdens

• No legitimate public health purpose

• FDA should approve all label changes before distribution

• Concern over confusion to public by temporarily having

multiple labels available for a single drug product

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• Not appropriate or realistic for ANDA holders to make

label proposals when they don’t have access to the full

complement of drug safety data, clinical studies and

FDA correspondence

• Are there alternative mechanisms rather than the CBE-0

supplement process, e.g., take enforcement action

against companies who are not updating their labels on

a timely basis?

• No timing specified for NDA holder to review the various

CBE-0 supplements or for FDA to act on the CBE-0

supplements 34



• No credible public health purpose • State law tort claims negatively affect quality and

efficacy of labeling

• ANDA holders lack necessary data

• Multiple, conflicting, simultaneous changes

• Health care providers don’t review ANDA labeling

• Which ANDA label should health care providers review?

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• Negative public health impact

• Confuse healthcare providers

• Competitors with different labels

• Deter prescription of generic products

• Inhibit generic substitution

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Comments Challenging Changes

Under FDA Statutory Authority


Comments Challenging Changes Under

FDA Statutory Authority

• A number of comments question FDA statutory

authority

• Statute requires sameness between NDA and

ANDA labels. 21 U.S.C. §355(j)(4)(G); 21 U.S.C.

§355(j)(2)(A)(v) (“the labeling proposed for the new

drug is the same as the labeling approved for the

listed drug”)

• The Proposed Rule authorizes and compels

differences; not FDA approved 38



FDA Statutory Authority (cont’d.)

FDA has consistently acknowledged that the

Federal Food, Drug, and Cosmetic Act does not

give it authority. E.g., U.S. amicus brief in Mensing;

1989 & 1992 rulemaking on ANDA regulations

under Hatch-Waxman

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“FDA does not believe that it would be consistent with the purpose of section 505(j) of the act, which is to assure the marketing

of generic drugs that are as safe and effective as their brand-name counterparts,




to interpret section 505(j)(2)(A)(v) of the act as permitting the marketing of generic drugs with diminished safety or effectiveness and concomitantly heightened labeled warnings.” (1989 Proposed Rule for ANDA regulations)

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• More recent amendments to FDA regulations

confirm ANDA product warnings may not

deviate from RLD approved labeling




• No “temporal” exception to sameness of

labeling under the statute

• No time limit under FDA’s Proposed Rule for

how long different labels for the same drug

product would be permitted to remain in

distribution

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• Supreme Court made clear in Mensing and

Bartlett that both legislative action and

subsequent agency rulemaking would be

required to implement changes set forth in the

Proposed Rule

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Prior Challenge to FDA Statutory

Authority for Proposed Regulation



Authority for Proposed Regulation

• 1998 “Pediatric Rule”

• Established presumption that not-yet-approved drugs

and biologicals should be studied in pediatric patients

• Authorized FDA to require pediatric studies for

marketed drugs and biological products that are used in

a substantial number of pediatric patients for claimed

indications or would provide meaningful therapeutic

benefit over existing treatments, and absence of

adequate labeling would pose significant risk

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Authority for Proposed Regulation (cont’d.)

• Waivers for pediatric testing available where testing is

impractical or impossible or evidence suggests drug

would be unsafe in pediatric patients

• Failure to comply could lead to enforcement action

deeming drug misbranded or unapproved

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• FDA pointed to various labeling and enforcement

provisions of FDCA and PHSA to support its

authority

• Requirements for adequate directions for use

• Prohibitions on false or misleading labeling

• Authority for enforcement actions if drugs not

recognized as safe and effective or not approved for

conditions recommended, suggested or prescribed in

labeling

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• Authority for FDA to require studies of marketed drugs

on grounds that absence of pediatric safety and

effectiveness information in the labeling renders the

products misbranded or an unapproved new drug

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• In 2000, challengers sought to enjoin

implementation of the Pediatric Rule, arguing FDA

did not have legal authority to require pediatric

studies. Ass’n of Am. Phys. & Surgeons, Inc. v.

FDA, 226 F. Supp. 2d 204 (D.D.C. 2002)

• District of D.C. concluded FDA did not have sufficient

authority to enact the rule

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• Tenuous relationship between labeling provisions and

rule’s requirement that manufacturers conduct studies of

drugs for unclaimed uses or devise formulations of the

drug tailored to those off-label uses

• In the interim, Congress enacted Best Protections for

Children Act (“BPCA”) which imposed a distinct regulatory

scheme (incentive scheme) to address pediatric drug

testing, demonstrating Congress’ intent to occupy the field

• The BPCA and Pediatric Rule were also incompatible with

one another

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• In the Proposed Rule, FDA relies upon

• statutory provisions under FDCA and PHSA that prohibit

false or misleading labeling

• misbranding provisions that require adequate directions

for use including adequate warnings and that deem a

product misbranded if dangerous to health when used in

the manner set forth in the labeling

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• premarket approval authority to require labeling to

permit the safe and effective use of the product

• authority to allow label changes by way of CBE-0

supplement for NDA and BLA holders

• mistaken belief that the recent Supreme Court cases do

not read the statute as prohibiting FDA from changing its

rules

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• But, similar to the Pediatric Rule case, the argument

can be made that there is no authority in existing

statutes for FDA to propose the rule

• Hatch-Waxman amendments require sameness

• No exceptions apply

• Rule allowing substantive labeling differences cannot be

authorized by FDA

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Potential Impact on Product

Liability Theories


Potential Impact on Product Liability Theories

• Creates possibility of failure to warn case law

against generic companies

• Did generic timely file a CBE-0 supplement?

• Did generic timely inform the public, patients and

providers of the label change?

• Was the warning adequate?

• Damages awards that eliminate years of sales

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Potential Impact on Product Liability

Theories (cont’d.)

• Creates possibility that NDA holders’ failure to

promptly adopt CBE-0 label changes by other

application holders could be the subject of litigation

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Conclusions

• What does the Proposed Rule Offer?

• Confusion of undetermined duration

• Significant compliance costs

• Increased legal fees

• Potential for substantial damages and settlement costs

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