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Over the Counter Drugs:
A Comprehensive Guide to the
Latest Development Affecting
Non-Prescription Drug Products
OTC Post Market Considerations:
Adverse Events, Safety
Communications and Label Warnings
Diane C. McEnroeSidley Austin LLP
October 29, 2015
Agenda
• Adverse Events
– Overview of Adverse Event Reporting
– When do reports trigger the need to submit a MedWatch form?
– Considerations during an investigation
• FDA’s Postmarketing Authority over OTC Drugs
– Safety Alerts
– OTC vs. Prescription Drugs
• Label Warnings and Safety Announcements
– What have we learned?
– Two Examples: Acetaminophen and Laxatives
SIDLEY AUSTIN LLP 2
Evolution of OTC Adverse Event Reporting Requirements
• Prior to 2007, only NDA and ANDA OTC drugs were subject to
mandatory postmarketing safety
• Effective December 22, 2007, the Dietary Supplement and
Nonprescription Drug Consumer Protection Act established reporting
requirements for OTC drugs not marketed under an approved
application, including those:
– Marketed under OTC Drug Monograph Review Process (whether or not
subject to a final monograph)
– Marketed outside the monograph system
– Discontinued from marketing but for which a report of an adverse event was
received
3
Defining Adverse Events in the OTC Space
• An adverse event (AE) is any health-related event associated with the
use of a drug in humans, including events occurring from:
– Use in professional practice
– Overdose (accidental or intentional)
– Abuse of the drug
– Withdrawal from the drug
– Any failure of expected pharmacological action
4
• Report on serious adverse events
• Serious adverse events are AEs that result in:
– Death;
– Life-threatening experience;
– Inpatient hospitalization;
– Persistent or significant disability or incapacity; or
– Congenital anomaly or birth defect
• Also includes AEs that, based on reasonable medical judgment, require medical or surgical intervention to prevent one of the above outcomes
Reportable v. Non-Reportable Events
5
NDA/ANDA Products: AE Sources
• NDA or ANDA applicant must review all AE information received from
any source, foreign or domestic, including:
– Consumer complaints
– Commercial marketing experience
– Postmarketing clinical investigations
– Postmarketing epidemiological or surveillance studies
– Reports in scientific literature
– Unpublished scientific papers
6
NDA/ANDA Products: 15-Day Alerts
• Applicant must submit reports of serious and unexpected adverse events no later than 15 calendar days after initial receipt of the information
– Reports in scientific literature, if they appear as case reports or as the
results of a formal clinical trial
– Reports from postmarketing studies, if the applicant concludes there is a
reasonable possibility that the drug caused the adverse event
• An unexpected adverse event is one that is not listed in the current
labeling for the drug product
– An event may be considered unexpected even if it may be anticipated from
the pharmacological properties of the product
7
NDA/ANDA Products: 15-Day Alerts
• Applicant must submit follow-up reports within 15 calendar days of receiving new information
• Non-applicants whose names appears on the label of an approved drug as a manufacturer, packer, or distributor also must submit 15-day reports
– May satisfy reporting obligation by submitting reports to the applicant within 5 days of receipt
8
NDA/ANDA Products: Periodic Reports
• NDA/ANDA applicant submits periodic adverse drug experience
reports (PADERs) for all AEs that are not serious and unexpected
– Quarterly for the first 3 years from the date of approval
– Thereafter, submitted annually
• Follow-up information may be submitted in the next PADER
• Upon written notice, FDA may extend or re-establish quarterly
reporting requirement
– E.g., after approval of a major supplement
9
• PADERs must contain:
– FDA Form 3500A for each adverse event
– Narrative summary and analysis, including analysis of 15-day Alert reports submitted during the reporting period
– Actions taken since last report because of AEs
• E.g., labeling changes, studies initiated
• PADERs do not contain reports from:
– Postmarketing studies
– Scientific literature
– Foreign marketing experience
NDA/ANDA Products: Periodic Reports
10
Monograph Products: SAER Submissions
• “Responsible Person” must submit serious adverse events associated
with use in the U.S. no later than 15 business days
– Responsible Person is any manufacturer, packer, or distributor whose
name appears on the label
• Retailer whose name appears on the label as a distributor may
authorize the manufacturer or packer to submit the required reports to
FDA
– Retailer must direct all AEs received to the manufacturer/packer
11
Monograph Products: SAER Submissions
• Statute limited to complaints received through the address or phone
number on product label
– In practice, no such limitation
– Watch social media posts
• Submit follow-up reports within 15 business days of receiving new
information
– New medical information related to a previously submitted serious adverse
event, if received within 1 year of the initial report
12
OTC Reporting Requirements
NDA/ANDA Products Monograph Products
• 15-day reporting of serious and unexpected AEs
– Either foreign or domestic
• Additional periodic reporting for other adverse events
– Domestic only
• Applicant + Manufacturer, packer, distributor
• 15-day reporting of serious AEs
– Domestic only
• No periodic reporting; update information as required
• Responsible Person (manufacturer, packer, distributor)
13
Elements of a Case Report
• Individual case safety report
– Identifiable patient
– Identifiable reporter
– Suspect drug
– Adverse event
• May be submitted
electronically
• Include label
• Each report (FDA Form
3500A) refers to individual
patient or single publication
14
Elements of a Case Report (cont.)
• Identifiable patient: Sufficient information to indicate the existence of
a specific patient or customer
– E.g., age, gender, initials, DOB, name, patient ID number
– Do not submit names and addresses of individual patients
• Instead, assign unique code number to each ICSR (e.g., patient initials)
• Identifiable reporter: Sufficient information to indicate there is an
identifiable person who purports to have knowledge about the patient,
adverse event, and drug involved
– E.g., name, professional identifier, contact information
15
Elements of a Case Report (cont.)
• Suspect drug: Information on the active ingredient(s) used by the
patient
– Describe the known product attributes, e.g., dosage form, strength, color,
SKU, NDC, lot number
• Serious adverse event: Describe in terms of signs (including
abnormal laboratory findings), symptoms, or disease diagnosis
– FDA encourages attaching to the report:
• Hospital discharge summaries
• Autopsy reports
• Relevant laboratory data
• Other critical clinical data
16
Typical Case Report Issues
• Reporter
– Majority of reporters are consumers, not healthcare professionals
– Majority reported by phone
• Drug
– Difficulty remembering sufficient details of medication use
– Lot number key to verifying identity of suspect product
• Many OTC products are part of a product line with different formulations and/or ingredients
– Many cases involve multiple products, making identification of suspect (vs. concomitant medication) difficult
17
Typical Case Report Issues (cont.)
• Event
– Majority are not serious
– Inadequate signs/symptoms reported
– Consumers tend to describe all their health problems, not just problems related to the event
• Issues
– For many cases, confirmation from a healthcare professional that event is serious is not available
– Coding must be consistent to trend events
– Many events are “lack of effect” events
• May be difficult to determine real events vs. consumers trying to claim refund
18
Case Report Review
• Consumer Affairs handles initial intake
– Enters into central database
– Ideally, all subsidiaries, including foreign, enter information to the central
database
• Medical Affairs or third party evaluates event for seriousness
– Determinations should be consistent
• Regulatory decides whether to report event
• Periodic committee meetings to identify emergent trends, medical
issues
19
OTC Record Keeping Requirements
NDA/ANDA Products Monograph Products
• Records of all adverse events maintained for 10 years
• Failure to submit reports can result in withdrawal of application approval
• Records of all reports maintained for 6 years
• Must keep records of AEs not submitted to FDA
• Failure to submit reports can result in monetary fines, product seizure, injunctions, and/or criminal penalties
20
FDA Inspections
• Section 704(a)(1) of the FDCA authorizes FDA to inspect, upon written notice:
• During inspection, FDA may access:
any factory, warehouse, or establishment inwhich … drugs … are manufactured, processed,packed, or held, for introduction into interstatecommerce or after such introduction …
all things therein (including records, files, papers,processes, controls, and facilities) bearing onwhether … nonprescription drugs intended forhuman use … are adulterated or misbranded…
21
• Key inspection issues:
– Late submission of reports and follow-up information
– Misclassifying and/or downgrading reports to non-serious without
reasonable justification
– Lack of training of pharmacovigilance staff and/or contractors
– Failure to maintain records of adverse events, including source documents
for each report
– Failure to determine root cause for late reporting and implement appropriate
corrective actions
FDA Inspections
22
Benchmarking Your Reporting and Record Keeping
Policies Against Competitors
• Train personnel to
gather as much
detail as possible
on the initial call
• Record all
attempts to obtain
additional
information about
the event
• Review AEs
not identified
as SAEs
• Review
complaints not
identified as
AEs
• Promptly
investigate
Thorough Intake Quality Control Timeliness
23
Benchmarking Your Reporting and Record Keeping
Policies Against Competitors
• Persons with medical
experience review
events to determine
if serious
• Document
justification for not
reporting any AEs
• Trend AEs
periodically
• Review FDA AER
and MDR databases
for competitor
reports
• Are you being more
or less conservative
than your
competitors?
Medical Expertise Assess
24
• Common pitfalls
– Inadequate intake
– Late submissions
– Failure to evaluate SAEs received from foreign subsidiaries
– Late 15-day reports from extended deliberation over whether an event is
“serious”
Benchmarking Your Reporting and Record Keeping
Policies Against Competitors
25
Adverse Events: Considerations During an Investigation
• Proper Intake Is Essential to Timely Filing
– Train on intake procedures; a script can help
– Keep a current list of products marketed
– Follow up calls can prove difficult
• Watch for trends; communicate well with manufacturing/quality to ensure
complaints are connected to production issues
– FDA will do this if you do not
• Sometimes offensive communications with FDA on upticks in SAERs can
prove beneficial to the company
– How many is too many?
• Bring in medical or outside experts to help with assessment when
needed
SIDLEY AUSTIN LLP 26
Postmarketing Surveillance Under FDAAA
• Prior to FDAAA, FDA’s ability to regulate drug safety was limited
– High bar for FDA to withdraw approvals
• No authority to mandate postmarketing clinical studies or make label
changes
• FDAAA enhanced FDA’s power regarding postmarket safety of drugs
− Postmarketing studies
− Labeling changes
− Risk Evaluation and Mitigation Strategies (REMS)
• Misbranding now includes failure to comply with postmarketing clinical
study requirements and REMS obligations, FDCA 303(f).
SIDLEY AUSTIN LLP 27
Postmarketing Surveillance
• FDA Adverse Event Reporting System (FAERS)
– Public FDA database of all adverse event reports and medication errors
submitted to FDA; predated FDAAA
• Document Archiving, Reporting, and Regulatory Tracking System
(DARRTS), created as part of FDAAA – to establish a Postmarket Risk
Identification and Analysis System, FDCA 505(k)(3).
– Internal FDA system that creates an entry for any “significant safety issue”
• Any safety issue with the potential to lead to withdrawal of approval, limitations on
use, safety-related labeling changes, or safety–related postmarketing trials
– Each entry is a “Tracked Safety Issue” (TSI)
• A TSI can be created as a result of adverse event reports, or can arise from
regulatory filings, literature, or other sources
SIDLEY AUSTIN LLP 28
FDA Postmarketing Authority: Safety Alerts
• Quarterly posting of potential signals of serious risks and new safety
information is mandated
– Derived from DARRTS but only includes issues based, at least in part, on
adverse event reports
• Continuous posting of “Safety Alerts” for all FDA-regulated medical
products
– Part of MedWatch data base
– Of 54 drug-related safety alerts issued January through September 2015, four
relate to OTC drugs
SIDLEY AUSTIN LLP 29
FDA Postmarketing Authority: OTC vs. Prescription
• FDA can require postmarket studies and safety labeling changes, but
only for prescription drugs.
– 426 studies requested since 2007, all but two involved prescription drugs
– Both OTC studies were for the same drug: Lilly’s Humulin 70/30
• Unique product sold behind the counter
• FDA can also require a Risk Evaluation and Mitigation Strategy (REMS)
but again, only for prescription drugs.
SIDLEY AUSTIN LLP 30
Lessons Learned
Acetaminophen
• Marketed under both NDA and Monograph
• Marketed OTC and Rx
• Multiple Drug Safety Communications and Actions
– 2004-2009: Scrutiny on Acetaminophen products related to liver damage;
rulemaking to establish new label warnings for OTC monograph products
containing acetaminophen
– 1/13/2011 Drug Safety Communication: Prescription Acetaminophen products
to be limited to 325 mg Per Dosage Unit
– 12/22/2011: Drug Safety Communication: Addition of another concentration of
liquid acetaminophen marketed for infants
– 8/1/2013 Drug Safety Communication: Association with risk of serious skin
reactions
SIDLEY AUSTIN LLP 31
Warning Labels: Lessons Learned
• OTC and Rx products separately addressed– Prescription Drugs:
• FDA may require any NDA holder of an Rx drug to update its labeling to include new
safety information; has the power to hold up supplements if no compliance
• In 2011, FDA required new boxed warning concerning liver injury to prescription
acetaminophen products
– OTC Drugs: • No comparable authority to require labeling changes for safety – notice and
comment rulemaking to revise the monograph to strengthen label warnings
• Example of the Dichotomy: 2013 Safety Alert on skin reactions:– “FDA will require that a warning be added to the labels of prescription drug
products containing acetaminophens”
– “FDA will also request that manufacturers add a warning . . . to the product
labels of OTC acetaminophen drug products marketed under an NDA and will
encourage manufacturers of drug products marketed under the OTC
monograph do the same”
SIDLEY AUSTIN LLP 32
Warning Labels: Lessons Learned
Laxatives
• 1/8/14 Safety Communication: FDA warns of possible harm from
exceeding recommended dose of over-the-counter sodium phosphate
products to treat constipation
– Explicitly based on (1) FAERS data from 1969 through 2012 and (2) medical
literature from 1957 through 2013
– Ten serious adverse events were reported through FAERS; 44 published in
literature
Takeaways:
– FDA can, and will, look beyond FAERS to determine whether a safety issue
exists
– Safety Communications get the word out - rulemaking needed to make it
formal for OTC monograph products; NDA OTCs may be subject to additional
pressure
SIDLEY AUSTIN LLP 33
Conclusion
• FDA has expanded post marketing authority to ensure drug safety
• Most provisions apply to prescription drugs, but FDA does have a way to
reach OTC as well, particularly those with NDA’s
• Serious Adverse Event Reporting must be taken seriously….
– FDA can initiate public discussions based upon SAERs filed in MedWatch or
as part of a product NDA
– Other information can add to safety concerns indicated by the FAERs data
base
• FDA’s power of publicity may be stronger than any formal legal power
SIDLEY AUSTIN LLP 34
Questions?
SIDLEY AUSTIN LLP 35
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