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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.

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Presentation on theme: "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."— Presentation transcript:

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 3

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 4

5 ADR Reports - Terms “Serious” 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 5

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 6

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 7

8 FDA 3500 and 3500A Forms 8

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 9

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) 10

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 11

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 12

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) 13

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 14

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). 15

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 16

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. §

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) 18

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) 19

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) 20

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) 21

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) 22

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) 23

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 24

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,

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. §

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 27

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 28

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

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 30

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 31

32 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 Phone: Thank you! Questions? Please contact: 32


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