FDLIIntroduction to Drug Law Regulation By Marc J Scheineson Esq Alston amp Bird 950 F Street NW Washington DC 20004 202 2393465 marcscheinesonalstoncom November 7 2013 ID: 753414
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Post-Approval Drug Issues
FDLI-Introduction to Drug Law Regulation
By:
Marc J. Scheineson, Esq.
Alston & Bird
950 F Street, N.W.
Washington, D.C. 20004
(202) 239-3465
marc.scheineson@alston.com
November 7, 2013
New Brunswick, NJSlide2
2
2Slide3
Introduction
Adverse drug experience (
ADR) reports15-day alert reports
Periodic ADR reportsAnnual and other reportsPost-approval changes/supplements
Grounds for withdrawal of approval
Sale/transfer of NDAs/ANDAs
Post-approval safety issuesPedigree/track-trace
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ADR Reports
Any “adverse event” associated with use of a drug in humans, whether or not considered drug-related
Can be associated with:
Normal useDrug overdose or abuseWithdrawalFailure of expected pharmacological action
Applicants to develop written procedures for handling and submitting
ADRs
to FDARx drugs without NDAs covered by 21 C.F.R. §310.305 (written procedures not required)
Serious Adverse Event
(AE) Reporting
now required for OTC monograph drugs
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ADR Reports - Terms
“Serious” means:
DeathLife-threatening adverse experience
Hospitalization (or prolonging hospitalization)Persistent or significant disability/incapacityCongenital anomaly/birth defect“Important medical event” that may jeopardize a patient“Unexpected” means:Not listed in current labeling
May be related to
event
listed in current labeling, but more severe or more specific5Slide6
15-Day Alert Reports
Applicant must report
AEs that are both “serious” and “unexpected” no later than 15 calendar days after initial receipt of information
Company must promptly investigate and submit follow-up reports to FDANon-applicant named on label (manufacturer, packer, distributor) must report AEs to applicant within 5-days or directly to FDA
If Rx, no NDA, notified manufacturer must
report
even if not named on label6Slide7
15-Day Alert Reports (cont.)
Based on scientific literature?
Only if case report or results of formal clinical trialSubmit copy of published
articleBased on post-marketing study?Only needed if “reasonable possibility” that drug caused adverse experience
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FDA 3500 and 3500A
Forms
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ADR Reporting
MedWatch
– Form FDA 3500AProvide as much information as known, but at least:
Identifiable patientIdentifiable reporterSuspect drug productAdverse eventDisclaimer permitted
Report does not constitute
admission
that drug caused or contributed to adverse event9Slide10
ADR Proposed Rule
March 14, 2003
Proposed Rule Require expedited reporting in more circumstances (
e.g., actual and potential medication errors)Change focus to Suspected Adverse Drug ExperiencesImprove harmonization of international reporting standardsMany potential changes to timing and types of reportingComment period extended; no final action yet (none projected)
Final rule issued for reporting AEs during clinical trials (9/29/10) – effective March 28, 2011 (enforcement delayed until September 28, 2011)
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Periodic ADR Reports
AEs
not considered “serious” and “unexpected” must be reported:Quarterly for 3-years
after drug approvalAnnually thereafterFDA may establish more frequent intervalReport must include:Narrative summary and analysis of 15-day reports submitted;Form 3500A for non-15-day
ADRs
; and
History of actions taken in response to ADRs11Slide12
ADR Enforcement
Failure to submit 15-day
reportsFailure to submit reports within 15-days
Failure to conduct follow-up investigation and submit 15-day follow-upFailure to submit periodic reportsFailure to have adequate written procedures for surveillance, receipt, evaluation, and reporting12Slide13
NDA Field Alert Reports
Mandatory reporting of:
Any incident causing a product or its labeling to be mistaken for, or applied to, another articleAny bacteriological contamination, or significant chemical, physical, or other change or deterioration in
distributed productAny failure of distributed product to meet specificationsNotify FDA District Office within 3 working days after receiving information
21 C.F.R.
§
314.81(b)(1)13Slide14
Annual Reports
21 C.F.R.
§314.81(b)(2
)Summary of significant new information that might affect safety, effectiveness, or labelingDistribution dataCurrent labeling
Chemistry, manufacturing, and control
changes
Nonclinical lab studiesClinical dataStatus report on post-marketing studies
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Annual Reports
21 C.F.R. § 314.80(c)(2) (requiring adverse drug experience reports quarterly for the first three years after approval of the application and then annually).
21 C.F.R. § 314.81(b)(2) (requiring an annual report “within 60 days of the anniversary date of approval of the application”).
21 C.F.R. § 314.98(c) (requiring an annual report for ANDA’s).
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Other Information
Submission of promotional materials
Representative copies at time of initial dissemination (Form 2253)
Withdrawal of approved drug from saleNotify FDA within 15 working daysSole manufacturer of life supporting drug, life sustaining or intended to prevent serious disease or condition - must notify FDA at least
6-months
before discontinuing manufacture
[Existing regulation; also part of FDASIA]Establishment registration (electronic)Update annually; PDUFA fee
Drug product listing (electronic)
Update every
6-months; PDUFA fee
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Post-Approval Changes/Supplements
NDA/ANDA holder must notify FDA about any “change in a condition established in an approved application beyond the variations already provided for” in
applicationAssess whether advance approval is needed to implement
changeFact-specific analysis21 C.F.R. §314.70
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Post-Approval Changes/Supplements (cont.)
“Prior approval” (major)
Changes in formulation, manufacturing process, packaging materials
“Changes being effected” (moderate)30-days: packaging change that doesn’t affect drug qualityImmediate: addition of specification, certain labeling changes to improve safe useLabeling standard changed effective Sept. 22, 2008“Annual report” (minor)
Delete color; adopt
compendial
changeDraft FDA Guidance (June 2010)18Slide19
Withdrawal of Approval
FDC Act
§505(e)
5 Mandatory bases (“shall”)3 Discretionary bases (“may”)
21 C.F.R.
§314.150(b
)Additional “regulatory” bases not in statuteFormal process requires administrative hearing (substantial effort by FDA
)
Statutory basis for reinstating approval when “the facts so require”
FDC Act
§505(f
)
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Withdrawal - Mandatory
Safety - clinical or other evidence shows drug
unsafe
Safety - based on new clinical evidence not in NDA or known to FDA that drug “is not shown to be safe”E.g., VIOXX Cox-2 NSAID (2004)E.g., Seldane (following Allegra approval)
E.g.,
Avastin
for breast cancer (2011)Effectiveness - new evidence shows lack of substantial evidence of effectiveness
Failure to file required patent
information
Application includes untrue statement of material fact
E.g., KV Pharmaceutical (1998)
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Withdrawal - Discretionary
Failure to have system for maintaining required records, to permit access to records, or to file required
reports
New information: serious manufacturing deficiencies and not corrected within reasonable time after written notice
New information: labeling is false or misleading and not corrected within
reasonable
time after written noticeGeneric MiraLax (Rx/OTC marketing) (October 2008)
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Withdrawal - Regulatory
Legal authority uncertain (but not challenged)
Failure to submit bioavailability or bioequivalence data
Failure to explain omission of investigation or other information pertinent to evaluation of drug (omission itself not basis for withdrawal)
Good laboratory practice violations
Informed consent/Institutional Review Board (IRB) violations
Refusal to permit inspection (applicant or contract research organization)
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Withdrawal - Others
Voluntary – applicant request
Product no longer marketed (e.g., Redux
)Failure to meet post-marketing endpoints (e.g., Iressa, Oforta, one indication for Celebrex)“Voluntary” – FDA request
Safety issues with
post-market
trial (e.g., Mylotarg, Meridia)Citizen PetitionRaising alleged safety concerns
Confusion over product names
“Imminent hazard” to public health
Summary suspension with opportunity for expedited hearing
HHS Secretary’s decision - only used once (late 1970s
)
Agency “mistake” (
American Therapeutics
case)
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Withdrawal – Others (cont.)
Advisory Committee
recommendationDarvon/Darvocet (propoxyphene) (
1/09)AdCom voted to withdraw approval based on safety issuesFDA (July 2009): no withdrawal – strengthened label, Medication Guide, additional safety studyFDA (Nov. 2010): based on new data, requested withdrawal;
manufacturer
agreed
Vicodin, Percocet (narcotics + acetaminophen) (6/09)AdCom voted to withdraw approval; no FDA action yet24Slide25
Withdrawal – Others (cont.)
“Administrative Reconsideration”
Spear Pharmaceuticals – fluorouracil ANDA approved April 11, 2008
Valeant Citizen Petition (denied); lawsuit against FDAFDA announced reconsideration May 14, 2008 due to “outstanding questions regarding this approval”Approval stayed until May 30, 2008 (Spear agreed to stay)
No indication
what
issues were uncoveredNo additional delay in approval beyond May 30, 2008
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Sale/Transfer of NDA/ANDA
Notify FDA at time of
transferLetter from former owner confirming transfer of rights
Letter from new owner:Providing commitment to meet conditions of applicationConfirming effective date of transferCertifying possession of full copy of application21 C.F.R. §314.72
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Post-Approval Safety Issues
New FDA authority to require:
Post-market studiesChange in label safety information
Risk Evaluation and Mitigation Strategy (REMS)Penalties for noncompliance:Misbranded drugCivil money penalties27Slide28
Risk Evaluation: FDA’s Risk Evaluation and Mitigation Strategies (REMS)
REMS is a safety strategy to manage a known or potential serious risk associated with a medicine
Mandated under 2007 Food and Drug Administration
Amendments
Act (FDAAA)
Gave FDA authority to require REMS from manufacturers to ensure that benefits of a drug or biologics outweigh its risk
May be required by FDA as part of new approval or when new safety information arises
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Pedigree Issues
“Pedigree” – statement to purchaser identifying each prior sale of drug (wholesalers/distributors
)Federal requirements delayed indefinitely (
RxUSA case)No pedigree needed from “authorized distributor of record” (ADR)No requirement to give pedigree to non-ADR (Catch-22)30+ States with pedigree laws (varying terms)Generally, ADRs must supply pedigrees outside normal distribution
Florida – electronic pedigrees now
California – effective 2016
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Track-Trace
Guard against counterfeits/poor quality
FDA Counterfeit Drug Task Force formed July 2003Task Force report issued February 2004
FDA Amendments Act of 2007:FDA to develop standards for “effective technologies” to secure drug supply chainFDA developed “standardized numerical identifier” to identify drug and allow track/trace (March 2010 guidance)October 2011 – final guidance on “physical-chemical identifiers” in solid oral dosage forms to prevent counterfeiting
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Track and Trace (cont.)
Legislation in final stages of passage/enactment
H.R. 1919, S. 957 Drug Supply Chain Security ActPreempts state law “inconsistent, more stringent or in addition to” Federal requirementsRequires manuf. to affix “product identifiers” on each package and homogeneous case of drug product (4-yrs. after enactment)
Pass lot-level transaction info. in paper or electronic form (1-yr. after enactment)Only engage in transactions with “authorized” trading partnersMaintain systems to verify product identifierMaintain systems to remove “suspect” or “illegitimate” product from supply chain
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DISCLAIMER: This presentation
and
the accompanying discussion provide general information on recent legal and regulatory developments. They are not intended to be, and should not
be, relied
upon
as
legal advice.
Marc J. Scheineson
Partner
Alton & Bird
LLP
950 F Street, N.W.
Washington, DC
20004
Phone:
202-239-3465
Email:
marc.scheineson@alston.com
Thank you!
Questions? Please contact:
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