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Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
ACI’s 2nd Annual Legal and
Regulatory Summit on Generic Drugs
FDA’s Proposed Generic Labeling
Rule and its Ramifications
Delphine W. Knight Brown
Partner
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
Labeling Rule – the Backdrop
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
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
3
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
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
4
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
Labeling Rule – the Backdrop (cont’d.)
• 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
5
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
Labeling Rule – the Backdrop (cont’d.)
• 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
6
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
Labeling Rule – The Details
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
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
8
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
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
9
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
Labeling Rule – The Details (cont’d.)
• 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
10
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
Labeling Rule – The Details (cont’d.)
• 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
11
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
Labeling Rule – The Details (cont’d.)
• 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
12
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
Labeling Rule – The Details (cont’d.)
• 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
13
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
Labeling Rule – The Details (cont’d.)
• 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
14
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
Labeling Rule – The Details (cont’d.)
• 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
15
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
Labeling Rule – The Details (cont’d.)
• 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
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA’s Proposed Generic Drug
Labeling Rule – The Details (cont’d.)
• 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
17
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
• 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
18
FDA’s Proposed Generic Drug
Labeling Rule – The Details (cont’d.)
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Creation of FDA Webpage
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
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
20
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
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
21
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
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
22
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
FDA Evaluation of CBE-0
Supplements
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
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
24
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
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
25
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
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
26
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Potential New Obligations for
ANDA and NDA holders
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
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
28
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Potential New Obligations for ANDA
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)
29
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Potential New Obligations for ANDA
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
30
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Comments on the Proposed Rule
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
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
32
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
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
33
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Comments on the Proposed Rule (cont’d.)
• 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
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Comments on the Proposed Rule (cont’d.)
• 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?
35
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Comments on the Proposed Rule (cont’d.)
• Negative public health impact
• Confuse healthcare providers
• Competitors with different labels
• Deter prescription of generic products
• Inhibit generic substitution
36
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Comments Challenging Changes
Under FDA Statutory Authority
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
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
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Comments Challenging Changes Under
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
39
“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,
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Comments Challenging Changes Under
FDA Statutory Authority (cont’d.)
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)
40
• More recent amendments to FDA regulations
confirm ANDA product warnings may not
deviate from RLD approved labeling
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Comments Challenging Changes Under
FDA Statutory Authority (cont’d.)
• 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
41
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Comments Challenging Changes Under
FDA Statutory Authority (cont’d.)
• 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
42
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Prior Challenge to FDA Statutory
Authority for Proposed Regulation
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Prior Challenge to FDA Statutory
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
44
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Prior Challenge to FDA Statutory
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
45
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Prior Challenge to FDA Statutory
Authority for Proposed Regulation (cont’d.)
• 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
46
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Prior Challenge to FDA Statutory
Authority for Proposed Regulation (cont’d.)
• 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
47
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Prior Challenge to FDA Statutory
Authority for Proposed Regulation (cont’d.)
• 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
48
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Prior Challenge to FDA Statutory
Authority for Proposed Regulation (cont’d.)
• 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
49
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Prior Challenge to FDA Statutory
Authority for Proposed Regulation (cont’d.)
• 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
50
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Prior Challenge to FDA Statutory
Authority for Proposed Regulation (cont’d.)
• 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
51
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Prior Challenge to FDA Statutory
Authority for Proposed Regulation (cont’d.)
• 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
52
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Potential Impact on Product
Liability Theories
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
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
54
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
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
55
Axinn, Veltrop & Harkrider LLP | New York | Washington, DC | Connecticut | Axinn.com
Conclusions
• What does the Proposed Rule Offer?
• Confusion of undetermined duration
• Significant compliance costs
• Increased legal fees
• Potential for substantial damages and settlement costs
56