1. 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
(202)
November 7, 2013
New Brunswick, NJ

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3. Introduction Adverse drug experience (ADR) reports
15-day alert reports
Periodic ADR reports
Annual and other reports
Post-approval changes/supplements
Grounds for withdrawal of approval
Sale/transfer of NDAs/ANDAs
Post-approval safety issues
Pedigree/track-trace

4. ADR Reports
Any “adverse event” associated with use of a drug in humans, whether or not considered drug-related
Can be associated with:
Normal use
Drug overdose or abuse
Withdrawal
Failure of expected pharmacological action
Applicants to develop written procedures for handling and submitting ADRs to FDA
Rx drugs without NDAs covered by 21 C.F.R. § (written procedures not required)
Serious Adverse Event (AE) Reporting now required for OTC monograph drugs

5. ADR Reports - Terms “Serious” means: “Unexpected” means: Death
Life-threatening adverse experience
Hospitalization (or prolonging hospitalization)
Persistent or significant disability/incapacity
Congenital 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 specific

6. 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 FDA
Non-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 label

7. 15-Day Alert Reports (cont.)
Based on scientific literature?
Only if case report or results of formal clinical trial
Submit copy of published article
Based on post-marketing study?
Only needed if “reasonable possibility” that drug caused adverse experience

8. FDA 3500 and 3500A Forms

9. ADR Reporting MedWatch – Form FDA 3500A
Provide as much information as known, but at least:
Identifiable patient
Identifiable reporter
Suspect drug product
Adverse event
Disclaimer permitted
Report does not constitute admission that drug caused or contributed to adverse event

10. 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 Experiences
Improve harmonization of international reporting standards
Many potential changes to timing and types of reporting
Comment 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)

11. Periodic ADR Reports
AEs not considered “serious” and “unexpected” must be reported:
Quarterly for 3-years after drug approval
Annually thereafter
FDA may establish more frequent interval
Report 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 ADRs

12. ADR Enforcement Failure to submit 15-day reports
Failure to submit reports within 15-days
Failure to conduct follow-up investigation and submit 15-day follow-up
Failure to submit periodic reports
Failure to have adequate written procedures for surveillance, receipt, evaluation, and reporting

13. NDA Field Alert Reports
Mandatory reporting of:
Any incident causing a product or its labeling to be mistaken for, or applied to, another article
Any bacteriological contamination, or significant chemical, physical, or other change or deterioration in distributed product
Any failure of distributed product to meet specifications
Notify FDA District Office within 3 working days after receiving information
21 C.F.R. §314.81(b)(1)

14. Annual Reports 21 C.F.R. §314.81(b)(2)
Summary of significant new information that might affect safety, effectiveness, or labeling
Distribution data
Current labeling
Chemistry, manufacturing, and control changes
Nonclinical lab studies
Clinical data
Status report on post-marketing studies

15. Annual Reports
21 C.F.R. § (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. § (b)(2) (requiring an annual report “within 60 days of the anniversary date of approval of the application”).
21 C.F.R. § (c) (requiring an annual report for ANDA’s).
FDA Guidance for Industry identifies information that need to be reported in annual reports
For CMC (Chemistry, Manufacturing and Controls) Post-Approval Manufacturing Changes, reportable information includes (with non-exhaustive examples)
Components and compositions (new suppliers, change in formulation)
Manufacturing sites (modifications to facilities, manufacture of additional drug products)
Manufacturing process (replacement of equipment, changes to filtration process parameters)
Specifications (change to drug substance)
Container/closure systems (use of contract manufacturing organization to supply product stoppers, change to a crimp cap)

16. Other Information Submission of promotional materials
Representative copies at time of initial dissemination (Form 2253)
Withdrawal of approved drug from sale
Notify FDA within 15 working days
Sole 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

17. 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 application
Assess whether advance approval is needed to implement change
Fact-specific analysis
21 C.F.R. §314.70

18. 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 quality
Immediate: addition of specification, certain labeling changes to improve safe use
Labeling standard changed effective Sept. 22, 2008
“Annual report” (minor)
Delete color; adopt compendial change
Draft FDA Guidance (June 2010)

19. Withdrawal of Approval
FDC Act §505(e)
5 Mandatory bases (“shall”)
3 Discretionary bases (“may”)
21 C.F.R. § (b)
Additional “regulatory” bases not in statute
Formal process requires administrative hearing (substantial effort by FDA)
Statutory basis for reinstating approval when “the facts so require”
FDC Act §505(f)

20. 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)

21. 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 notice
Generic MiraLax (Rx/OTC marketing) (October 2008)

22. 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)

23. 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 Petition
Raising 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)

24. Withdrawal – Others (cont.)
Advisory Committee recommendation
Darvon/Darvocet (propoxyphene) (1/09)
AdCom voted to withdraw approval based on safety issues
FDA (July 2009): no withdrawal – strengthened label, Medication Guide, additional safety study
FDA (Nov. 2010): based on new data, requested withdrawal; manufacturer agreed
Vicodin, Percocet (narcotics + acetaminophen) (6/09)
AdCom voted to withdraw approval; no FDA action yet

25. Withdrawal – Others (cont.)
“Administrative Reconsideration”
Spear Pharmaceuticals – fluorouracil ANDA approved April 11, 2008
Valeant Citizen Petition (denied); lawsuit against FDA
FDA 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 uncovered
No additional delay in approval beyond May 30, 2008

26. Sale/Transfer of NDA/ANDA
Notify FDA at time of transfer
Letter from former owner confirming transfer of rights
Letter from new owner:
Providing commitment to meet conditions of application
Confirming effective date of transfer
Certifying possession of full copy of application
21 C.F.R. §314.72

27. Post-Approval Safety Issues
New FDA authority to require:
Post-market studies
Change in label safety information
Risk Evaluation and Mitigation Strategy (REMS)
Penalties for noncompliance:
Misbranded drug
Civil money penalties

28. 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
On 9/27/07, the Food and Drug Administration Amendments Act of 2007 (FDAAA) (Public Law ) was signed into law. Title IX, Subtitle A, Section 901 of this statute created new section of the FDCA. which authorizes FDA to require persons submitting certain applications (applicants) to submit a proposed REMS as part of such application if the FDA determines that a REMS is necessary to ensure that the benefits of a drug outweigh the risks of the drug.
Section applies to applications for approval of prescription drugs submitted under FDCA subsections 505(b) or (j) and applications submitted under section 351 of the Public Health Service Act. These applications are termed covered applications and refer to new drug applications (NDAs), abbreviated new drug applications, (ANDAs), and biologics license applications (BLAs).  
Section also authorizes FDA to require holders of covered applications approved without a REMS to submit a proposed REMS if the FDA becomes aware of new safety information as defined in 505-l(b)(3) and determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks of the drug. Once the holder of an approved covered application is notified by FDA that a REMS is necessary, the holder must submit a proposed REMS within 120 days, or within such other reasonable time as FDA requires to protect the public health (section 505-1(a)(2)(B)).
REMS submissions – DETAILED -- includes: timetable for submission of assessments (18 mos./3 years after the strategy is approved, for example), additional potential elements (medication guide, a patient package insert if insert helps mitigate a serious adverse event, communication plan to HCPS), ETASU (Elements to Ensure Safe Use) (if drug is shown to be effective, but associated with a serious adverse event)  

29. 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

30. Track-Trace Guard against counterfeits/poor quality
FDA Counterfeit Drug Task Force formed July 2003
Task Force report issued February 2004
FDA Amendments Act of 2007:
FDA to develop standards for “effective technologies” to secure drug supply chain
FDA 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

31. Track and Trace (cont.)
Legislation in final stages of passage/enactment
H.R. 1919, S. 957 Drug Supply Chain Security Act
Preempts state law “inconsistent, more stringent or in addition to” Federal requirements
Requires 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 partners
Maintain systems to verify product identifier
Maintain systems to remove “suspect” or “illegitimate” product from supply chain

32. Thank you! Questions? Please contact:
Marc J. Scheineson
Partner
Alton & Bird LLP
950 F Street, N.W.
Washington, DC
Phone:
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.