Transcript OTC Drug Product Pharmacovigilance

OTC Drug Product
Pharmacovigilance
Timothy R. Dring
Johnson & Johnson
Pharmaceutical R&D
Overview
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III.
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IV.
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V.
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VI.
Introduction
Regulatory Status
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NDA'ed drugs
B.
Monograph'ed drugs
Typical characteristics of OTC drug ADE case reports
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Initial reporter
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Drug
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Event
Issues
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Medical confirmation
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Event and term coding
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Labeling
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Lack of effect
OTC Drug Product Pharmacovigilance
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Organization
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Case review and handling
FDA Inspections
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Late reports
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Source documentation
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Labeledness determinations
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Standard Operating Procedures
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Database and computer system validation
Disclaimer
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This presentation is reflective of
my past experience when
employed with a particular OTC
drug company, and may not
necessarily be reflective of the
practices at other OTC drug
companies
Introduction
Similarities to Rx Drugs
 Pharmacologic action and unintended side effects
 Procedures for the collection and reporting of case
information
Differences from Rx Drugs
 Detail and veracity of case information
 Lack of health professional involvement
 Lack of labeling with detailed safety information; i.e.,
physician's package insert
 Ancillary issues and requirements (e.g., consumer
affairs/refund type issues)
U.S Regulatory Status
NDA'ed OTC Drug Products
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E.g., Rx-to-OTC switch drugs
Expedited Reporting
Same requirement as for Rx drug products; i.e., serious/unlabeled
cases must be reported within 15 calendar days
Periodic Reporting
Same requirement as for Rx drug products
Monograph’ed drugs
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No NDA; marketed subject to FDA therapeutic category monograph
No requirement for expedited or periodic reporting; proposed FDA rule
likely to require expedited reporting for serious ADEs regardless of
labeledness, but no periodic reporting
FDA has, at times, requested that OTC drug companies prepare ad hoc
compilations and reports of serious/labeled and/or nonserious ADEs
to address safety issues
Typical Characteristics of OTC
Drug ADE Case Reports
Initial reporter
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Majority (>2/3) are consumers rather than health professionals, many of whom
have little or no scientific or medical education or background
Some are relatives or friends of the subject of the ADE, rather than the patient
Majority of initial contacts are by phone, particularly if product has a toll-free
phone number listed on the package
Drug
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Identification of the suspect medication not always exact
OTC products are not prescribed, nor is use recorded in a medical record
Difficulty with consumer remembering sufficient details of medication use
Many OTC drug products are part of a line of products in the same therapeutic
category under the same overall brand name, but which may have different
formulations and/or ingredients
Lot number critically important for verifying identity of suspect medication and
exposure
Many cases involve multiple medication use, both Rx and other OTC drugs,
making identification of suspect medications (versus concomitant medications)
difficult
Typical Characteristics of OTC
Drug ADE Case Reports
Event
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Majority of cases are non-serious
Inadequately specific signs/symptoms typically reported
Initial reporters who are not health professionals (i.e., the majority of
reporters) are not adequately versed in medical diagnosis and
associated terminology (e.g., how do you deal with a complaint that
the consumer just "felt awful" after product use?)
Consumers tend to describe all of their health problems, not just
events related specifically to the medication in question
Signs and/or symptoms of sufficient detail and specificity available
only upon further probing and investigation, particularly with the
consumer's physician, if the physician is even aware of the event to
begin with
Some cases involve brief emergency department visits, rather than
hospitalizations, which may not meet “serious” criteria
Accidental pediatric exposures often involve patients who are
asymptomatic without sequelae
Issues
Medical Confirmation
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For all serious cases, confirmation of the ADE is attempted by contacting the
treating physician and/or hospital in writing
For many of the cases where the initial reporter was not a health professional,
confirmatory information from a health professional is not available or (if
available) released
Event and Term Coding
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Many consumer-reported signs/symptoms are not adequately mapped to
appropriate ADE terms in the older thesauri; MEDDRA is a vast improvement in
this regard, but still with some limitations
Problem with evaluating series of similar cases if coding is inconsistent or terms
are imprecise
Labeling
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OTC product labels contain significantly abbreviated safety information in
consumer lay language rather than the detailed information contained in a
physician's package insert, particularly for monograph’ed products
Problems with defining the labeledness of an event if it is not described
specifically on the package label, but yet is part of the known side effect profile
for the particular active ingredient (e.g., as described in official compendia)
Issues
Lack of effect
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Many OTC product complaints relate to an alleged "lack of
effect"
Many OTC indications for use can be complicated by other coexisting conditions or diseases, making self-medication
difficult; this is particularly true when self-medicating severe
cold/flu symptoms
OTC products may not necessarily produce the same degree of
efficacy measurable by consumer-recognizable or objective
clinical endpoints as with RX drugs
Many OTC consumers have unreasonable efficacy expectations
or take an OTC product for reasons other than those described
in the labeling
Many OTC consumers are simply attempting to get a refund by
claiming the product "did not work" for them
Regulatory definition of "lack of effect" relates more to frank
pharmacological failure rather than to cases of general
consumer dissatisfaction typically seen with OTC products;
difficult to distinguish true lack of effect cases from general
consumer complaints
OTC Drug Product
Pharmacovigilance at a Larger OTC
Drug Company
Organization
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Primary responsibility typically lies with Medical Affairs Dept. with assistance from
Consumer Affairs, Regulatory Affairs, and Quality Assurance
May have multiple sites that perform pharmacovigilance activities
Typically have links to prescription drug division pharmacovigilance functions
Case review and handling
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Letters and telephone calls initially received by Consumer Affairs and passed on to
Medical Affairs if medical complaint involved; primary focus on cases concerning
serious ADEs
All contacts entered into central database, which has multiple modules for Medical
Affairs (medical information), Consumer Affairs (non-medical, non- technical complaint
information), and Quality Assurance (technical complaints)
ADE Review Committee consisting of representatives from Medical Affairs, Consumer
Affairs, Regulatory Affairs, and Quality Assurance meets every two weeks to review all
new cases in database and verify appropriateness of handling and reporting, as well
as to identify and track any emergent trends or medical issues
Expedited reports receive special handling and are reviewed and approved by Medical
Director and Regulatory Affairs prior to filing
Adherence to a formal Standard Operating Procedure
FDA Inspections
OTC drug companies have undergone FDA inspection of their U.S. pharmacovigilance
activities. The following are the key inspection issues:
Late Reports
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Problem with meeting filing deadlines for serious, unlabeled ADE reports, particularly
of foreign origin
Source Documentation
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Even if ADE database is fully computerized, all documents and correspondence related
to an ADE case must also be kept in paper form, which FDA considered to be the true
source documentation, and which must be properly date-stamped
Labeledness Determinations
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Determinations of labeledness more straightforward with Rx drugs (i.e., physician
package inserts provide specific, detailed information regarding possible side effects);
not so with OTC drugs
Company policy may be to base determinations of labeledness not only on the
information contained on the OTC label, but also on information contained in
standard, peer-reviewed and regularly updated compendia if such information is well
known and documented for the particular OTC active ingredient in question; for Rxto-OTC switches, reference can be made to the original physician's package insert;
use CIOMS-formatted core safety data sheets for reference purposes
FDA Inspections
Current Standard Operating Procedures
 FDA expects to see a current,
adequately detailed SOP that delineates
line function responsibilities and
procedures
Database and Computer System
Validation
 FDA requires that any computer
database for ADE data undergo a formal
validation
Pharmacoepidemiology
Studies
Examples of detected signals/trends that resulted in
fielding a new PE study:
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Serious cardiovascular ADEs associated with nicotine patches
for smoking cessation, leading to execution of: 1) a crossdesign synthesis study of existing data; 2) a case-control
study; and 3) upon OTC switch, establishment of consumer
registry/cohort for collecting safety information
Hemorrhagic strokes associated with use of products
containing phenylpropanolamine, leading to: 1) evaluation of
background rate of hem. stroke in the US and a calculation of a
standardized morbidity ratio; and 2) a case-control study
Problems reported with use of bulk fiber laxatives and certain
Rx medications, leading to an independent PE review of
available published and unpublished clinical data, with
resultant label changes
Recalls
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Lot number identification critical in assessing any complaints
suggestive of an adverse trend in product quality or safety
Most OTC drug companies conduct an annual product review
to trend medical and technical complaints by lot number of
product; governed by cGMP regulations that apply to OTC
drugs
Periodic reviews of ADEs and trends can also identify product
and/or labeling problems
Some problems identified in the course of annual stability
testing, possibly requiring issuance of an FDA Field Alert notice
and possible recall
Decision to recall is a voluntary one by industry; FDA does not
have statutory authority to force a recall, but can seize
defective product
Important Points
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Analysis of safety trends reliant on quality and consistency of data associated
with individual case reports contained in FDA Med Watch/AERS database,
company databases, and in the medical literature
With products for which there is no mandatory safety information collection
and reporting requirement, there may be issues with the quality of available
safety information between sources (FDA, industry, other)
Ability of a product marketer/manufacturer to appropriately collect and
process reported safety information depends greatly on the availability and
allocation of personnel and financial resources (i.e., some OTC firms are part
of a large corporate structure, where resources are available, and some are
very small independent firms with few or no in-house scientific/medical
personnel)
Consider use of third-party organizations or contractors to handle
pharmacovigilance activities