OTC Drug Product Pharmacovigilance

1
OTC Drug Product Pharmacovigilance

• Timothy R. Dring
• Johnson Johnson
• Pharmaceutical RD

2
Overview

• I. Introduction
• II. Regulatory Status
• A. NDA'ed drugs
• B. Monograph'ed drugs
• III. Typical characteristics of OTC drug ADE case
  reports
• A. Initial reporter
• B. Drug
• C. Event
• IV. Issues
• A. Medical confirmation
• B. Event and term coding
• C. Labeling
• D. Lack of effect
• V. OTC Drug Product Pharmacovigilance
• A. Organization
• B. Case review and handling
• VI. FDA Inspections
• A. Late reports
• B. Source documentation

3
Disclaimer

• 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

4
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)

5
U.S Regulatory Status

• NDA'ed OTC Drug Products
• 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
• Monographed drugs
• 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

6
Typical Characteristics of OTC Drug ADE Case
Reports

• Initial reporter
• Majority (gt2/3) 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
• 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

7
Typical Characteristics of OTC Drug ADE Case
Reports

• Event
• 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

8
Issues

• Medical Confirmation
• 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
• 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
• 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 monographed 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)

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Issues

• Lack of effect
• Many OTC product complaints relate to an alleged
  "lack of effect"
• Many OTC indications for use can be complicated
  by other co-existing 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

10
OTC Drug Product Pharmacovigilance at a Larger
OTC Drug Company

• Organization
• 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
• 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

11
FDA Inspections

• OTC drug companies have undergone FDA inspection
  of their U.S. pharmacovigilance
• activities. The following are the key inspection
  issues
• Late Reports
• Problem with meeting filing deadlines for
  serious, unlabeled ADE reports, particularly of
  foreign origin
• Source Documentation
• 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
• 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 Rx-to-OTC
  switches, reference can be made to the original
  physician's package insert use CIOMS-formatted
  core safety data sheets for reference purposes

12
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

13
Pharmacoepidemiology Studies

• Examples of detected signals/trends that resulted
  in
• fielding a new PE study
• Serious cardiovascular ADEs associated with
  nicotine patches for smoking cessation, leading
  to execution of 1) a cross-design 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

14
Recalls

• 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

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Important Points

• 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