otc post market considerations: adverse events, safety

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

[email protected]

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– Unpublished scientific papers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



• 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”



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).


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


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


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.


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


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”


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


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


Questions?


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