OUR LADY OF FATIMA UNIVERSITY

College of Pharmacy

POST MARKETING SURVEILLANCE

 Unit Outcomes
To demonstrate understanding of FDA drug
approval process, more specifically,
• Recall the flow of process on FDA approval
process
• Discuss the important process of the FDA
review process
• Discuss the strategies for premarketing
activities
 Checklist
• Read unit outcomes and unit objectives
• Read course guide prior to class attendance
• Proactively participate in discussions
• Watch videos related to the topic
• Participate in discussion board (Canvas)
• Answer and submit course unit tasks
 Required Readings
• https://www.intechopen.com/books/pharmacov
igilance/introductory-chapter-pharmacovigilance
(Introductory Chapter: Pharmacovigilance)
DISCOVERY AND DEVELOPMENT

PRECLINICAL RESEARCH

CLINICAL RESEARCH

FDA REVIEW
FDA POST MARKET SAFETY
MONITORING
An overview of the drug discovery, development and approval process.
PHASE IV STUDIES:
POST MARKETING SURVEILLANCE
• is the term used for the monitoring of a drug after it has received
approval and has reached the market.
• It is designed to evaluate the long-term safety and efficacy of a drug,
potential “real-world” problems with formulation, and use for
unapproved conditions or “off-label” (e.g. use in an age group or at a
dosage outside of that advised in the product label).
• Phase IV studies are conducted after approval of the drug has been
granted.
• Number of participants: Several thousand.
• The volunteers will be diagnosed with the condition/disease that the drug is
approved to treat.
• The purpose of a Phase IV study is to obtain additional information about the
long-term risks and benefits of taking a drug now that it is being more
widely used. The “real-world” data can also help determine if there is scope
to develop the drug further, for example:
§ To explore use of the drug for additional indications/ additional age
groups
§ To develop an alternative route of administration
FDA Post-Market Drug Safety Monitoring
Ø Even though clinical trials provide important information on a
drug’s efficacy and safety, it is impossible to have complete
information about the safety of a drug at the time of approval.
Ø Despite the rigorous steps in the process of drug
development, limitations exist. Therefore, the true picture of a
product’s safety actually evolves over the months and even
years that make up a product’s lifetime in the marketplace.
FDA Post-Market Drug Safety Monitoring
Ø FDA reviews reports of problems with prescription
and over-the-counter drugs, and can decide to add
cautions to the dosage or usage information, as well
as other measures for more serious issues.
FDA Post-Market Drug Safety Monitoring
Ø Following drug approval and manufacturing, the FDA requires
drug companies to monitor the safety of its drug using the
FDA Adverse Event Reporting System (FAERS) database.
Ø FAERS helps FDA implement its post-marketing safety
surveillance program. Through this program, manufacturers,
health professionals, and consumers report problems with
approved drugs..
FDA Post-Market Drug Safety Monitoring

SUPPLEMENTAL APPLICATIONS
Ø Developers must file a supplemental application if they wish
to make any significant changes from the original NDA.
Ø Generally, any changes in formulation, labeling, or dosage
strength must be approved by FDA before they can be made.
 FDA Post-Market Drug Safety
Monitoring
INDs FOR MARKETED DRUGS
Ø If sponsors want to further develop an approved drug for a
new use, dosage strength, new form, or different form (such
as an injectable or oral liquid, as opposed to tablet form), or if
they want to conduct other clinical research or a post-
market safety study, they would do so under an IND.
 FDA Post-Market Drug Safety
Monitoring
MANUFACTURER INSPECTIONS
Ø If sponsors want to further develop an approved drug for a
new use, dosage strength, new form, or different form (such
as an injectable or oral liquid, as opposed to tablet form), or if
they want to conduct other clinical research or a post-
market safety study, they would do so under an IND.
 FDA Post-Market Drug Safety
Monitoring
DRUG ADVERTISING
Ø FDA regulates prescription drug advertisements and promotional labeling.
By law, a developer is prohibited from advertising unapproved uses of their
product.
Ø All advertisements, such as product claims or reminder ads, cannot
be false or misleading. They must contain truthful information about a
drug’s effectiveness, side effects, and prescribing information. These
advertisements can be found in medical journals, newspapers, and
magazines, and on the Internet, television, or radio.
 FDA Post-Market Drug Safety
Monitoring
DRUG ADVERTISING
Ø Promotional labeling differs from drug advertisements in the
way it is distributed. Pharmaceutical companies give out
brochures or other promotional materials to physicians or
consumers. The drug’s prescribing information must accompany
promotional labeling.
 FDA Post-Market Drug Safety
Monitoring
GENERIC DRUGS
Ø New drugs are patent protected when they are approved for
marketing. This means that only the sponsor has the right to
market the drug exclusively.
Ø Once the patent expires, other drug manufacturers can develop
the drug, which will be known as a generic version of the drug.
 FDA Post-Market Drug Safety
Monitoring
GENERIC DRUGS
Ø Generic drugs are comparable to brand name drugs and must
have the same:
ü Dosage form
ü Strength
ü Safety
ü Quality
ü Performance characteristics
ü Intended use
 FDA Post-Market Drug Safety
Monitoring
GENERIC DRUGS
Ø Because generic drugs are comparable to drugs already on
the market, generic drug manufacturers do not have to
conduct clinical trials to demonstrate that their product is
safe and effective. Instead, they conduct bio-equivalence
studies and file an Abbreviated New Drug Application.
 FDA Post-Market Drug Safety
Monitoring
REPORTING PROBLEMS
Ø FDA has several programs that allow manufacturers, health
professionals, and consumers to report problems associated
with approved drugs.
§ MedWatch is a gateway for reporting problems with
medical products (drugs and devices) and learning about
new safety information.
 FDA Post-Market Drug Safety
REPORTING PROBLEMS
Monitoring
Ø FDA has several programs that allow manufacturers, health
professionals, and consumers to report problems associated with
approved drugs.
§ Medical Product Safety Network (MedSun) monitors the safety and
effectiveness of medical devices. FDA recruits 350 healthcare providers
throughout the United States to report any medical device problems that result
in serious injury or death. Each month, FDA publishes the MedSun newsletter. The
newsletter gives consumers important information about medical device safety.
 FDA Post-Market Drug Safety
Monitoring
ACTING SURVEILLANCE
Ø Under the Sentinel Initiative, FDA is developing a new national system
to more quickly spot possible safety issues. The system will use very
large existing electronic health databases—like electronic health
records systems, administrative and insurance claims databases, and
registries—to keep an eye on the safety of approved medical products
in real time. This tool will add to, but not replace, FDA's existing
postmarket safety assessment tools.
 PHARMACOVIGILANCE
The science and activities relating to the detection,
assessment, understanding, and prevention of
adverse effects or any other drug-related
problems.
DIVISION OF PHARMACOVIGILANCE

• Evaluate the safety of drug and therapeutic biologic products

• Advance public health by detecting and analyzing safety signals from all
available data sources, utilizing evidence based methods
• Recommend appropriate regulatory actions, including
labeling changes, Risk Evaluation and Mitigation Strategies
(REMS), etc.
• Communicate relevant safety information
Safety Evaluators
§ 10 teams of SEs
– Majority clinical pharmacists
– Provide critical analysis of sources of postmarketing data to
identify and evaluate safety signals
§ Team coverage aligned with the Office of New Drugs (OND)
review divisions’ therapeutic areas
– ~ 4-7 SEs per team (including Team Leader)
– Each SE covers assigned product group(s) aligned with therapeutic
area
Medical Officers (MO)
§ Provide clinical expertise in various therapeutic areas such
as dermatology, oncology, rheumatology, etc.
§ Collaborate with DPV teams on safety evaluation
§ Collaborate with Office of New Drugs (OND) on safety
evaluation
LIMITATIONS OF PREMARKTETING
CLINICAL TRIALS
• Size of the patient population studied
• Narrow population - often not providing sufficient data
on special groups
• Narrow indications studied
• Short duration
BENEFITS OF POSTMARKETING
MONITORING
The ability to study the following:
• Low frequency reactions (not identified in clinical trials)
• High risk groups
• Long-term effects
• Drug-drug/food interactions
• Increased severity and / or reporting frequency of
known reactions
TYPES OF POSTMARKETING SURVEILLANCE
q Spontaneous/voluntary reporting of cases
– National (FDA MedWatch)
– Local or Regional (Joint Commission Requirement)
– Scientific literature publications
q Postmarketing studies (voluntary or required)
– Observational studies (including automated healthcare
databases)
– Randomized clinical trials
q Active surveillance
– Drug-Induced Liver Injury Network (DILIN)
– Sentinel initiative
How Postmarketing Reports Get to FDA
Patients, Consumer, and Healthcare
Professionals

Voluntary Voluntary

FDA MedWatch Manufacturer

Regulatory
requirements
5% of all
reports FDA

FAERS 95% of all

Database reports
Postmarketing Safety Reporting Requirements
q Under 21 CFR 314.80 postmarketing safety reports must be
submitted to the agency for the following:
§ 15-day Alert reports: Serious and unexpected adverse experience
from all sources (domestic and foreign)
§ Periodic Adverse Events Reports: Domestic spontaneous adverse
events that are:
- Serious and expected
- Non-serious and unexpected
- Non-serious and expected
- Quarterly for the first 3 years then annually
Serious Adverse Event
Results in any of these outcomes:
§ Death
§ Life-threatening adverse experience
§ Inpatient hospitalization – new or prolonged
§ Persistent/significant disability/incapacity
§ Congenital birth defect
§ Other serious: based upon appropriate medical judgment, they
may jeopardize the patient and require intervention to
prevent a serious outcome
SPONTANEOUS REPORTS
§ A communication from an individual (e.g., health care professional, consumer) to a
company or regulatory authority
§ Describes a suspected adverse event(s)
§ Passive and voluntary reports

FACTORS AFFECTING REPORTING

§ Media attention
§ Litigation (class action lawsuits)
§ Nature of the adverse event
§ Type of drug product and indication
§ Length of time on market
§ Extent and quality of manufacturer’s surveillance system
§ Prescription or over-the counter (OTC) product status
§ Reporting regulations
 FDA ADVERSE EVENT REPORTING SYSTEM
§ Computerized database
§ Spontaneous reports
§ Contains human drug and therapeutic biologic reports
§ > 9 million reports since 1969
§ Over 1.2 million new reports in 2014
 WHAT IS SAFETY SIGNAL?
§ Reported information on a possible causal relationship
between an adverse event and a drug
§ The relationship being previously unknown or incompletely
documented.
§ Usually supported by multiple case reports
§ New unlabeled adverse events
§ An observed increase in a labeled event OR a greater severity
or specificity
§ New interactions
§ Newly identified at-risk population
SOURCES OF POSSIBLE SAFETY SIGNALS
§ Routine pharmacovigilance
§ FAERS
§ Data mining
§ Periodic Safety Update Reports from drug manufacturers
§ Study results
§ Medical literature
§ Media
§ New Drug Application (NDA)
§ Safety database
§ Outside inquiry
§ Foreign Regulatory Agencies
§ Others
 DATA MINING
§ Mathematical tool identifies higher-than-expected frequency
of product-event combinations
§ Tool for hypothesis generation
§ Supplements FAERS data review
§ Does not replace expert clinical case review
Reporting to MedWatch
Reporting to MedWatch
Consumer MedWatch Form

q MedWatch Form 3500B

q Includes 4 primary components
• Patient
• Product
• Event
• Reporter
q User-friendly format for non-
health care professionals
 Components of a
Good Postmarketing Report
§ Description of adverse event
§ Suspected and concomitant product therapy details (e.g., dose, dates of
therapy)
§ Patient characteristics (e.g., age, sex), baseline medical condition,
comorbid condition, family history, other risk factors
§ Documentation of the diagnosis
§ Clinical course and outcomes
§ Relevant therapeutic measures and laboratory data
§ Dechallenge and rechallenge information
§ Reporter contact information
§ Any other relevant information
Developing a Case Series
§ Identify a well-documented case in FAERS, published
literature, data mining, or other sources to identify a safety
signal.
§ Using our knowledge of the clinical course of the disease,
formulate a case definition which may include both clinical
features and laboratory findings, sometimes even
demographic information if we believe the safety signal is for
a specific population.
§ Complete a thorough database search for additional cases.
Principles of Case Evaluation
§ Temporal relationship
§ Causality assessment
• Certain
• Probable/Likely
• Possible
• Unlikely
• Conditional/Unclassified
§ Key factors in causality assessment including, but not limited to
• Dechallenge/rechallenge
• Comorbidities
• Concomitant medications
• Consistent with pharmacological effects ( biologic plausibility)
RELATED LINKS AND VIDEOS:
• https://www.youtube.com/watch?v=yYSqNZP30sM (Post
Marketing Surveillance | Clinical Development of Drug |
Clinical Research |)
• https://www.youtube.com/watch?v=ZtSilyJ182Q (Post-
Marketing Drug Safety Surveillance)
• https://ww2.fda.gov.ph/index.php/issuances-2/pharml-
1/pharml-fda-circular/15838-fc-2013-004 (Post Marketing
Surveillance, FDA Philippines)
• https://www.who.int/medicines/regulation/ssffc/pms/en/
(Essential Medicines and Health Products)