Transcript Pharmacovigilance

Pharmacovigilance
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The New Drug Development Process:
Steps from Test Tube to New Drug Application Review
▪ FDA estimates 8 year time-span for entire process
▪ Pharmaceutical industry claims $802 million spent for each new drug brought to market
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Courtesy: www.fda.gov/cder/handbook/develop.htm, 2007.
Learning Objectives
• Pharmacovigilance and Global Pharmacovigilance System
• Individual Case Safety Reports (ICSRs), AEM form, CIOMS and
Medwatch
• Case processing and Reporting
• Medical dictionary (MedDRA) and Medical aspects in
Pharmacovigilance
• Special cases in Pharmacovigilance
• Medical Information System
• Safety monitoring in Clinical Trials
• Signal detection
• Periodic Safety Update Reports (PSURs) and suspected unexpected
serious adverse reactions (SUSARs)
• Medication errors, Risk –benefit assessment and management in
Pharmacovigilance
• Standard Operating Procedures in Pharmacovigilance
• Compliance monitoring and Pharmacovigilance inspections
• Global regulatory affairs and their requirements and related guidelines
in Pharmacovigilance
• Pharmacovigilance communications
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• Pharmacoepidemiology
Pharmacovigilance
The science and activities relating to the
Detection, Assessment, Understanding
and Prevention of adverse effects or any
other medicine-related problem - WHO
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Vigilance
• Vigilare = to watch
–alert watchfulness
– forbearance of sleep; wakefulness
–watchfulness in respect of danger; care;
caution; circumspection
–the process of paying close and
continuous attention
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Adverse Event
An unwanted or harmful reaction
experienced following the administration
of a drug or combination of drugs under
normal condition of use and suspected
to be related to the drug.
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Common ADRs
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•
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Constipation after Codeine
Sedation with Antihistamine
Nausea with Fluaxetine
GIT upset with NSAIDs
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▪ 1959 / 61–Thalidomide 4.000 –
10.000 cases (Phocomelia)
Medicines are supposed to save lives
Dying from a disease is sometimes unavoidable;
dying from a medicine is unacceptable. WHO.
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Geneva 2005
Drug Outcomes
» Outcomes:
•
•
•
Effects (Pharmacological, therapeutic)
Side effects (Unintended)
Interactions (Expected, unexpected)
» Impact:
•
•
Beneficial
Harmful
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Harmful Effects
• Mortality
• Morbidity
» Hospitalization
» Prolonged stay
» Extra treatment
• Cost
»Resources consumed
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Need for PVG
• Limited value of animal experiments in
predicting human safety
• Clinical trials are limited in time and
number of individuals (a few hundred),
usually under favorable conditions, i.e. in
the hospital, under close surveillance, over
a short period, with few concomitant
medications, and with few high-risk
individuals (e.g. children, older individuals,
pregnant women, or patients with renal or
hepatic failure)
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Populations not studied in the
pre-approval phase
•
•
•
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Children
The elderly
Pregnant or lactating women
Patients with co-morbidity such as hepatic
or renal disorders
• Sup-populations carrying known and
relevant genetic polymorphisms
• Patients of different racial and/or ethnic
origins
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Drug Development
Clinical development of medicines
Phase I
20 – 50 healthy volunteers
to gather preliminary data
Animal experiments for
acute toxicity, organ
damage, dose dependence,
metabolism, kinetics,
carcinogenicity,
mutagenicity/teratoge nicity
Preclinical
Animal
Experiments
Phase I
Development
Phase III
250 – 4000 more varied
patient groups – to
determine short-term safety
and efficacy
Phase II
150 – 350 subjects with
disease - to determine
safety and dosage
recommendations
Phase II
Phase III
Phase IV
Post-approval studies to
determine specific safety issues
Phase IV Spontaneous
Post-approval
Reporting
Post Registration
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Need for PVG
• Rare or delayed serious reactions are likely to remain
unnoticed
• Rare ADRs (occurring for instance in 1/1000 individuals)
are unlikely to be identified in pre-marketing studies.
Effects that are difficult, even impossible to detect
clinically
» Toxicity to Reproduction
» Genotoxicity
» Carcinogenicity
• A drug that belongs to a widely used pharmacological
class may be used in up to 100,000 individuals within the
first month, so that a rare but serious ADR may occur
only in few patients.
rare diseases occurs as very rare as rare
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Medication Errors
• Medication error is any preventable event
that may cause or lead to inappropriate
medication use or patient harm while the
medication is in the control of the health
care professionals, patient, or consumer.
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Key facts
• No medicine is risk free. Vigilant
assessment of the risks and benefits of
medicines promotes patient safety.
• People in every country of the world are
affected by ADRs. In some countries ADRrelated costs, such as hospitalization,
surgery and lost productivity, exceed the
cost of the medications.
• Unintended, harmful reactions to medicines
(known as adverse drug reactions) are
among the leading causes of death in many
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countries.
Medication Errors … .
USA
Drug related death rate: 19% due to adverse events in health care
50% preventable
United Kingdom
Adverse events in 10% of patients
50% preventable
1100 deaths in adverse drug events (low estimate)
Australia
Adverse events cause 16.6%of hospital admissions
Adverse drug events in 2-4%hospital admissions
Up to 75% potentially preventable
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•
1.
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3.
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5.
6.
7.
8.
Key
facts…
The majority of adverse drug reactions (ADR) are preventable and
can be due to:
Wrong diagnosis of the patient’s condition;
Prescription of the wrong drug or wrong dosage of the right drug;
An undetected medical, genetic or allergic condition that might
cause a patient reaction;
Self-medication with prescription medicines;
Not following the instructions for taking the medication;
Reactions with other drugs (including traditional medicines) and
certain foods;
Use of a sub-standard medication whose composition and
ingredients do not meet the correct scientific requirements, and
can be ineffective and often dangerous;
Use of counterfeit medicines with no active ingredients or the
wrong ingredients, which can be dangerous or fatal.
Prescribing & transcription – 60%;
Administration – 30%;
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Dispensing – 10%
Aims and Responsibilities
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•
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Early detection of unknown safety problems
Detection of increases in frequency
Identification of risk factors
Quantifying risks
Preventing patients/Public from being affected
unnecessarily
• Standard Requirements:
» Reporting
» Labelling
» Approach (Insert, package, etc)
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When PVG Starts
• Testing of drug safety always begins in
clinical trials. Before a medication reach
the market, it must go through several
stages of clinical trials to gauge the
potential risks and benefits associated with
the drug
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Adverse Reactions: Possible Causes
• Intrinsic factors of the drug
–
–
–
–
Pharmacological
Idiosyncratic
Carcinogenicity, Mutagenicity
Teratogenicity
• Extrinsic factors
– Adulterants
– Contamination
• Underlying medical conditions
• Interactions
• Wrong usage
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Outcome of PVG
• Contribute to the regulatory assessment of benefit, harm,
effectiveness and risk of medicines, encouraging their safe,
rational and more effective (including cost effective) use.
• Improve patient care and safety in relation to use of medicines
and all medical and paramedical interventions.
• Improve public health and safety in relation to use of
medicines.
• Promote understanding, education and clinical training in
Pharmacovigilance and its effective communication to the
public.
• The results of pharmacoepidemiological studies would confirm
or disprove the license
• Effectiveness of the drug in clinical practice (confirmation of
the therapeutic effect), determine whether approved uses
• Should be expanded or restricted
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Classification
Pharmacovigilance
Active
Passive
ADR
Cause
Severity
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Passive or active Pharmacovigilance?
Active PVG: Active (or proactive) safety
surveillance means that active measures are
taken to detect adverse events. This is managed
by active follow-up after treatment and the
events may be detected by asking patients
directly or screening patient records. The most
comprehensive method is cohort event
monitoring (CEM)
The essential and interesting tasks of causality
assessment and signal identification are
applicable to both methods of surveillance
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Passive or Active Pharmacovigilance?
Passive PVG: Passive surveillance means that no
active measures are taken to look for adverse
effects other than the encouragement of health
professionals and others to report safety
concerns. Reporting is entirely dependent on the
initiative and motivation of the potential
reporters. This is the most common form of
pharmacovigilance. It is commonly referred to as
“spontaneous” or “voluntary” reporting. In some
countries this form of reporting is mandatory
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ADVERSE DRUG REACTIONS TYPES BY CAUSE
• Type A: Augmented pharmacologic effects dose dependent and predictable
a. Intolerance
b. side effects
• Type B: Bizarre effects (or idiosyncratic) dose independent and unpredictable
• Type C: Chronic effects
• Type D: Delayed effects
• Type E: End-of-treatment effects
• Type F: Failure of therapy
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ADVERSE DRUG REACTIONS TYPES BY CAUSE
1.
Type A
Type A reactions are extensions of the
drug's known pharmacology
1.
Responsible for the majority of ADRs.
•
Type A reactions ate usually dose
dependent and predictable but can be
the result of concomitant disease
states, drug-drug interactions, or drugfood interactions.
•
•
Ways to minimize type A reactions
include understanding the
pharmacology of the drug being
prescribed, monitoring drugs with a
narrow therapeutic index, and
avoiding poly-pharmacy when
possible.
1.
Type B
Type B reactions are usually not the result
of a known pharmacology of the drug but
seem to be a function of patient
susceptibility.
1.
Uncommon but are generally serious and
can be life threatening.
•
They are rarely predictable, are usually not
dose dependent, and seem to concentrate
in certain body systems such as the liver,
blood, skin, kidney, and nervous system.
•
Type B reactions include idiosyncratic
reactions, immunological or allergic
reactions, and carcinogenic or teratogenic
reactions
•
Except for immediate hypersensitivity
reactions, type B reactions usually take 5
days before the patient demonstrates
hypersensitivity to a drug. There is no
maximum time for the occurrence of a
reaction, but most occur within 12 weeks of
initiation of therapy.
e.g. cough with ACE Inhibitors
e.g. cough with ACE Inhibitors
•
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When is an ADR serious?
• Death / life-threatening (real risk of dying)
• Hospitalization (initial or prolonged)
• Disability (significant, persistent
or permanent)
• Congenital anomaly
• Required intervention to prevent
permanent impairment or damage
• Causes malignancy and Malformations
• Medical and scientific judgment determines
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SAEs that may not need to be
recorded on an SAE
• Deaths due to disease in a study where
death is a primary endpoint
Example:
Death from stroke in a stroke trial
Death from Cancer in a caner trial
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Exceptions to hospitalization as SAEs
• In the absence of medical adverse event
• Admission for the treatment of a pre-existing
condition not associated with the development of a
new AE with a worsening of a pre-existing condition
• Social admission
• Administrative admission
• Protocol specified admission during the study
• Any other optional admission not related tot the AE
• Hospitalization for an event that is an endpoint
– MI, AIDS event, cancer recurrence
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Confirmation of case seriousness
Seriousness should not be changed if the
case
• Received as serious from an HCP
• Received from a license partner or
regulatory authority
• Clinical trial case that already reported as
serious
• MedDRA preferred critical term (coded as
always serious)
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Ratings by iGuard
While no official scale exists yet to communicate overall drug risk, the
iGuard Drug Risk Rating System is a five color rating scale similar to the
Homeland Security Advisory System
• High Risk (Red): Requires careful consideration of risk versus benefit
with your doctor.
e.g. Adriamycin, Vincristine
• Elevated (Orange): Create a personal risk reduction plan with your doctor
e.g. Prednisone, Warfarin, Insulin
• Guarded (Yellow): Reserved for new products, be on the lookout for
safety events
e.g. Januvia, Yaz
• General (Blue): Use under the normal care of your doctor
e.g. Lipitor, Lopressor
• Low (Green): Suitable for widespread use
e.g. Vitamin C, Caltrate
In the United States, the Homeland Security Advisory System is a color-coded
terrorism threat advisory scale
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Definitions
Term
Definition
Adverse Event (AE)
Any untoward medical occurrence in a Patient or Clinical
Trial Subject administered a medicinal product and which
does not necessarily have a causal link with the
treatment.
Adverse Reaction (AR) or
Adverse Drug Reaction (ADR)
Unexpected Adverse Reaction
(UAR)
SUSAR Suspected Unexpected
Serious Adverse Reaction
(SUSAR)
Any untoward and unintended responses to an
investigational medicinal product related to any dose
administered.
An adverse reaction, the nature or severity of which is not
consistent with the product information eg. Investigator
Brochure (IB) or Summary of Product Characteristics or
USPI or CDS
not listed in the protocol as an expected adverse reaction
and it occurs it is defined as a SUSAR
A Useful Hint: Minimise SUSARs by listing everything you know about the Dru33g
Examples of ADRs
Medicines
Reactions
Amidopyrine (for inflammation)
White blood cell disorder
Clioquinol (for skin infections)
Visual impairment
Erythromycin estolate (antibacterial)
Hepatitis (liver disorder)
Oral contraceptives
Thromboembolism (blood clots)
Statins (for controlling cholesterol)
Muscle degeneration
Thalidomide (for managing morning
sickness)
Phocomelia (disfigured infants)
Courtesy: WHOSIS
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TEN DRUGS WITH THE MOST REPORTED ADRs
NO
2002
2003
2004
2005
2006
2007
1
CO –
TRIMOXAZOLE
(47)
ALLOPURINOL (33)
ALLOPURINOL (37)
CAPTOPRIL
(52)
TRADITIONAL
MEDICINE
(68)
PERINDOPRIL (97)
2
CARBAMAZEPINE
(32)
CLOXACILLIN (30)
PARACETAMOL (29)
ALLOPURINOL (51)
DICLOFENAC
(65)
ALLOPURINOL (75)
3
CLOXACILLIN
(31)
MEFENAMIC ACID (25)
CARBAMAZEPINE (29)
CLOXACILLIN
(50)
CARBAMAZEPINE
(62)
CLOXACILLIN (71)
4
AMOXYCILLIN
(28)
DICLOFENAC
(24)
NIFEDIPINE
(28)
DICLOFENAC
(44)
NIFEDIPINE
(58)
DICLOFENAC (71)
5
ALLOPURINOL (22)
CHLOROTHIAZIDE (22)
CO – TRIMOXAZOLE
(28)
NIFEDIPINE
(44)
ALLOPURINOL (57)
METFORMIN (69)
6
TRADITIONAL
MEDICINE
(22)
CARBAMAZEPINE (19)
ERYTHROMYCIN (23)
METFORMIN
(39)
PERINDOPRIL (57)
ASPIRIN (67)
7
ALENDRONATE
(19)
TRADITIONAL
MEDICINE
(18)
AMOXYCILLIN
(23)
PARACETAMOL (38)
CO – TRIMOXAZOLE
(55)
8
DICLOFENAC
(19)
AMOXYCILLIN
(18)
MEFENAMIC ACID (21)
CO – TRIMOXAZOLE
(37)
ASPIRIN
(41)
RIFAMPICIN (46)
9
ISOSORBIDE
DINITRATE
(18)
PENICILLIN G SODIUM
(15)
ASPIRIN
(19)
ATENOLOL
(37)
ERYTHROMYCIN (40)
PHENYTOIN (44)
10
LOVASTATIN
(13)
VANCOMYCIN (15)
CLOXACILLIN (18)
CEFUROXIME
(36)
PHENYTOIN
(39)
TICLOPIDINE (50)
AMOXYCILLIN (43)
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ACTIVE INGREDIENTS WITHDRAWN
–
–
–
–
–
–
–
–
–
–
–
THALIDOMIDE (1961)
BENOXAPROFEN (1982)
PHENFORMIN (1982)
FENFLURAMINE (1997)
ASTEMIZOLE
PHENYLPROPANOLAMINE(2000)
KAVA KAVA
CERIVASTATIN
CISAPRIDE
ROFECOXIB (2004)
VALDECOXIB (2005)
– COMFREY, SENECIO
– TEGASEROD (2007)
– CLOBUTINOL (2007)
Congenital limb defects
Hepatotoxicity
Lactic acidosis
Heart-valve abnormalities
Many drug interactions
Haemorragic stroke
Liver abnormalities
Rhabdomyolysis
Cardiac arrythmias
Cardiovascular events
Cardiovascular events,
serious skin reactions
Nephrotoxicity
Cardiovascular events
Cardiac arrhythmia
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Functions of Pharmacovigilance
(WHO Guidelines, 2000)
• Detection and study of adverse reactions
• Measurement of risk and benefits
• Measurement of effectiveness and Monitoring
the impact of any corrective actions taken
• Benefit & harm evaluation
• Dissemination of information, education
►Early warning
► Rational and safe use of medicines
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WHO Response
•
WHO promotes global drug safety through its International Drug
Monitoring Programme, which began in the 1960s. Through the
cooperative effort, Member States and WHO work together to
identify possible relationships between the use of a drug and
adverse effects. Nearly 100 countries now have national systems in
place to report ADRs to the database managed by the WHO
Collaborating Centre, the Uppsala Monitoring Centre. When signals
of drug safety problems emerge, WHO shares the results with all
Member Countries.
In addition, WHO:
1.
Facilitates regular information exchanges among Member States on
the safety and effectiveness of medicines, involving a network of
national information officers;
2.
Promptly informs national health authorities about new information
on serious adverse effects of pharmaceutical products;
3.
Provides guidelines to help countries set up national drug
monitoring centers;
4.
Assists countries as they work to strengthen drug regulatory
authorities and reporting systems;
5.
Trains health professionals on safety monitoring for new and
complex medicines (e.g. antiretrovirals to treat HIV);
6.
Draws together regulatory authorities, police, customs officials and38
others to combat counterfeit medicines worldwide.
Pharmacovigilance Reporting
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Pharmacovigilance reporting requirements
Learning Objectives:
• Identify the minimum criteria for AEM
reporting
• Identify HCP reports
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Identifiable Patient
Suspect Product
Minimum
criteria for AEM
reporting
Adverse Event
Identifiable reporting
source
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Components of a case report
• Identifiable Patient: At least one of the details should
be available
(Age, DOB, sex, history, case identification i.e Patient ID)
• Product: Clearly refers to name of a drug or biologics or
any device
• Adverse event: (Sign, symptom, severity, diagnosis,
outcome, Action taken, dechallenge, rechallenge,
Laboratory data,, drug exposure (Dose, dosage,
concoms, Indication, overdose, misuse)
• Source: Identifiable reporter (Consumer/Patient, Legal
source)
Case follow-up for missing data
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Who Can Report?
- Any healthcare professional including
Physicians, Dentists, Nurses,
and Pharmacists, Coroners
- Voluntary registers
- Pharmaceutical Firms
- ADR Reporting systems/Camps
- Employees of physician or other HCP who contact the
company n behalf of physician
- HCP by local regulations (Physician assistant in US,
Psychologist in Germany)
- Literature reports from medical and scientific journals
- Clinical study report
- Regulatory agency reports (except where the reporter to the
regulatory agency is identified not to b an HCP i.e. like
consumer)
- Dr. Specialist, (Reports from unidentifiable experts)
- Other occupations/qualifications not previously mentioned44
How to Report
AEM or AE Reporting Form:
• Individually developed by each country that has set up a
Pharmacovigilance Centre
• To be effective should be available in the local language with
features relating it to the responsible authority e.g. a logo, and the
address and contact details of the issuing institution
Other options for reporting
• Telephone. Report receiver should have a reporting form
• E-mail. A written case report submitted by e-mail may be
acceptable. Further details can be obtained by follow-up.
Reporting forms can be sent to reporters as e-mail attach-ments
and faxed or mailed to the Pharmacovigilance Centre when
completed.
• Fax. Sending reports by fax is equivalent to mailing the report, but
faster. A fax machine is a very important asset for a national
Pharmacovigilance Centre and its major sentinel sites.
• The Internet. An Internet site is a valuable asset for a
Pharmacovigilance Centre and a reporting form could be made
available for downloading or for completion online (en-tering d4a5ta
through web-based data entry) if the site is secure.
Of which to report?
Medicinal Products covered
by Pharmacovigilance
activities includes,
• Centrally authorised
• Authorised through mutual
recognition procedure
• Purely nationally
authorised
• New medicinal products
(NCE), old medicinal
products
• Biologicals: vaccines, blood
products, others
• Herbal medicinal products
• Alternative and
complementary medicinal “..vegetable pills have taken root in my nose. It
was reddish before but now it is carotty”
products
Morrison’s universal vegetable pills, 1834/148634
What to Report?
•
»
»
»
»
»
»
»
All suspected reactions including
Unknown, Unexpected
Lack of effect
Counterfeiting
Resistance
Interaction
Dependence and abuse
Unexpected beneficial effects
• Excludes: (At risk and other special scenarios)
» Therapeutic failures
» Intentional/accidental poisoning, abuse
» Errors in administration
» Noncompliance
For New drugs, Report all suspected reactions including minor ones
Quality defects can also lead to ADRs
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When to report
• A report should be completed as soon as
possible after the reaction.
• It is better to advise reporters not to wait
until final results and information such as
hospital letters are received. These
additional details can be sent to the
Pharmacovigilance Centre later as a
Follow up item
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Follow-up when Necessary
•
All reports of serious events should be followed up if
details are incomplete. This may require the involvement
of health professionals trained and appointed for this
type of work.
• Occasionally follow-up information is required to fully
assess reports of non-serious events. Follow-up
requests should be kept to a minimum because they can
act as a deterrent to further reporting.
Examples
A request for essential missing details;
Information on the final outcome;
The result of rechallenge;
The results of laboratory tests;
Postmortem results, from health facilities where autopsy
is undertaken.
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Where To Report
• Reports should be sent to the
Pharmacovigilance Centre.
• If it is not practical to send the forms
directly to the centre, it may be necessary
to arrange points of collection at other
sites as e.g. specific hospitals or clinics.
• They should be stored securely to
maintain confidentiality.
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Who are the partners?
•
•
•
•
•
•
•
•
•
•
Government
Industry
Hospitals and academia
Medical and pharmaceutical associations
Poisons information centers
Health professionals
Patients
Consumers
Media
WHO
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PVG Reporting
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PVG Reports
Learning Objectives:
• Classification of AE reports
• Product labeling
• Difference between expected and unexpected
AES
• Causality Assessment
• Determine medically confirmed reports
• Special case scenarios (EIU, medical devices)
• Narrative writing
• Regulatory reports
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Methods in Pharmacovigilance
• Spontaneous Reporting: AE report from any
unsolicited source (Legal)
• Clinical studies
• Prescription Event Monitoring (Solicited
reports)
• Literature reports
• Registry reports
• Case Control Surveillance
• Record Linkage (automated population
databases; ‘data mining’)
• Medical device complains
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Advantages of Spontaneous Reporting
• Effective!
• Wide coverage (‘all patients, all drugs, all adverse reactions’)
• Continuous
• Rapid
• Cheap
Limitations of Spontaneous Reporting
• Suspicions
• Underreporting and bias
• Insensitive to type C adverse effects (Chronic)
• Drug consumption data available? (denominator)
• No quantitative assessment
• Comparison of drugs difficult
• No proof of causality
• Often further study needed (hypothesis testing, evaluation)
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Product Labeling/Listedness
assessment
• United States Package Insert (USPI), Core
Data Sheet (CD), Summary of Product
Characteristics (SPC)
IB_2
IB sample
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Expected Vs. unexpected
Expected AEs
• Consistent/synonymous
with AEs contained in
the labeling document
• Labeled, listed
depending on labeling
document used
Unexpected AEs
• Not
consistent/synonymous
with AEs contained in
the labeling document
• Not labeled, unlisted
depending on labeling
document used
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Listedness assessment
• The safety sections (Undesirable Effects /
Adverse Reactions, Warnings and
Precautions, Contraindications,
Interactions, Overdose, Effects on
Pregnancy and Lactation, Effects on
Driving and Operating Machinery, Drug
Abuse, and Dependence) of the product
labeling document are reviewed
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Listedness assessment
• Listedness assessments are based upon the event
term as coded.
• If the term(s) is not identical to that explicitly stated
in the product labeling document, but is medically
equivalent, the AE is considered listed.
Eg. Ischemic attack Vs Stroke
Infarction Vs Myocardial Infarction
Chest Pain Vs Angina
Breathing difficulties Vs Dyspnoea
• If the term(s) is a less severe presentation of a
listed term, the AE is considered listed.
Eg. Transient Ischemic attack
Severe Depression
Acute or Chronic Infarction
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Events Considered To Be Listed
• AEs included in the selected product labeling document
• AEs identified by the reporter as symptoms or consequences of a
listed event (e.g., the listed event of stroke resulting in
hemiplegia);
• Based on medical judgment, exacerbations of certain AEs (i.e.,
AEs in which the natural course of the disease include
exacerbation/quiescent periods, e.g., asthma, depression);
• All AEs in the selected document in cases of drug overdose;
• Reactions listed for a product continue to be considered listed
even when reported as the consequence of an interaction; and
• Fatal SAEs are considered listed when the selected product
labeling document specifically indicates that the SAEs could
result in death.
• “Drug Withdrawal Syndrome” (e.g., applicable to CNS products)
if “withdrawal symptoms” are mentioned in the selected
document or the AEs occurring upon drug withdrawal are part of
the normal signs and symptoms of the disease for which the drug
was indicated.
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Events Considered To Be Unlisted
• Events not included in the selected product labeling
document;
• All clinical study SAEs which are specifically associated
with an excipient of a placebo; and
• AEs that while included in a more general, listed event add
more specificity or are more severe (e.g., ‘infections' in the
labeling document would be less specific than ‘E. coli
infection’, bacterial septicemia);
• Fatal SAEs are considered unlisted when the selected
product labeling document does not specifically indicate
that the SAEs could result in death.
• “Drug Withdrawal Syndrome” if “withdrawal symptoms” are
not mentioned in the selected data sheet or the AEs are
not part of the normal signs and symptoms of the disease
for which the drug was indicated.
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Class Labeling
• If the AE as listed in the product labeling
document refers to drug class only, with no
specification that the event has been observed
with the case suspect product, and is not listed
in any other section of the product labeling
document, the AE is considered unlisted
• Eg.
Antihypertensives
Diuretics
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Special Patient Population
• If an adult, who does not meet the criteria
of a special patient population as identified
in the product labeling document,
experiences an AE that is listed only in the
section of the product labeling document
referring to AEs experienced by special
patient populations (e.g., pediatric,
patients with renal impairment, etc.), then
the AE is considered unlisted.
63
Reassessment of Listedness
• Reassessment of listedness of event(s) is
performed upon receipt of significant
follow-up that changes the medical
assessment (e.g., an event that becomes
fatal or life-threatening).
• Reassessment of listedness of event(s) is
not performed upon receipt of a follow-up
report [where no change in the event(s) is
reported], for the sole reason of the
product labeling document being updated.64
Causality Assessment
A medical judgement made by a qualified medical Practitioner
•
Is there a reasonable possibility that the serious
adverse event Is related to the study or suspect
product or clinical trial procedure?
1. How close is the relationship between drug and
event?
2. Did the drug cause the event?
•
•
YES -Related
NO - Unrelated
Final judgment will depends on Company and the reporter
65
Uses and limitation of Causality
Assessment
• What it can do?
-
-
Decrease disagreement between
accessor.
Classify uncertainty
Mark individual case reports
Improve the scientific basis of
assessment
66
What it cannot do?
• Give and accurate quantitative
measurement of the likelihood of a
relationship.
• Distinguish valid form invalid cases
• Quantify the contribution of a drug to the
development of an adverse event
• Change uncertainty to certainty
67
Methods of Causality
Assessment
There were several method that can be use to make a
causality assessment of ADRs reports.
• The literature (9 points of consideration – Morges,
Switzerland , 1981)
• Probability calculation (Bayes’ Theorem)
• Aetiological – Diagnostic Systems (Bénchiou’s
group method)
• French imputation systems
• The European ABO Systems
• The US Reasonable Possibility Systems
• The Naranjo ADR Probability Scale
• WHO Causality Categories
68
The literature (9 points of consideration –
Morges, Switzerland , 1981)
1.
2.
3.
4.
5.
6.
7.
8.
9.
Drug given prior to event?
Reaction at site of application?
Drug/ADR interval compatible with the event?
ADR immediately follows drug administration and is of
acute onset?
Rechallenge positive?
Dechallenge positive?
Were concomitant drugs stopped at the same time?
Same adverse reaction to this drug before?
Adverse reaction known with the suspected drug?
69
Causality Assessment
Not Related [The Adverse Event
is clearly not related to the
investigational agent(s)]
Unlikely Related [The
Adverse Event is doubtfully related to
the investigational agent(s)]
Possibly Related
[The Adverse Event may be related
to the investigational agent(s)]
Probably Related [The
Temporal relationship of the onset of the event,
relative to the administration of the product, is not
reasonable or another cause can by itself explain the
occurrence of the event.
A clinical event, including laboratory test
abnormality, with a temporal relationship to drug
administration which makes a causal relationship
improbable, and in which other drugs, chemicals or
underlying disease provide plausible explanations.
Again temporal relationship, relative, however is
reasonable but the event could be due to another,
equally likely cause.
Temporal relationship, relative, reasonable and more
likely explained by the product than any other cause
Adverse Event is likely related to the
investigational agent(s)]
Definitely Related [The
Adverse Event is clearly related to
the investigational agent(s)]
Temporal relationship, relative, reasonable and there
is no other cause to explain the event.
70
Medically Confirmed
• Report received from HCP, confirms the
occurrence of AE’s and does not deny the
relationship of the confirmed AE’s to the
company product
Case with at least one serious event will be considered as serious case
71
Special case scenarios
• At risk Situation
- Not associated with adverse event but involve a
circumstance that may increase the
patients/subjects risk or developing adverse
events (Associated events)
Eg. Drug misuse, EIU, Extravasations, Medication
error and Overdose
• Suspected transmission of infections agent (Any
Infections agent or pathogen transmitted via
product)
• Drug interaction
• Lack of Efficacy
72
Narrative Writing
• A concise, comprehensive written summary or all clinical
and relevant information relating the suspect with the
adverse events
Key elements:
• Source type and follow-up details (initial or FU #)
• Patients details
• Relevant patient social, medical and drug history
• Suspect/Co-suspect product (s) details
• Concomitants products
• Adverse events in details including outcome, Action
taken any treatment received
• Diagnosis and relevant laboratory details
Narratives should be framed in Chronological order and should
comply with the SOPs
73
Narrative Writing
• This is a “report type” from a consumer by way
of “source type”. This 00 year old male
consumer experienced Event or signs or
symptoms on “date”. His concomitants
includes …..The Relevant history
includes……Along with XXX he was also treated
with YYY from 00 to 00. As a result of the event,
he was hospitalized from 00 to 00. His
discharge medications includes.. and the
diagnostic report includes…. --------. He was re
hospitalized on 00 and he died on the same
day. The primary cause of death was noted as
…….The secondary cause associated for the
death reason were ……..Autopsy results shows
….
74
75
76
77
EDI: Electronic Data Interchange
78
79
COSTART - Coding Symbols for Thesaurus of Adverse Reaction Terms.
WHOART - WHO Adverse Reactions Terminology
80
81
82
83
84
85
Safety monitoring in Clinical Trials
86
Decision Tree for Data and Safety Monitoring for Clinical Trials
Human Subjects involved? (even if exempted under 45 CFR 46)?
YES
NO
Data and Safety Monitoring Policy and
Guidance do not apply
Is a Clinical Trial proposed (any Phase) ?
YES
NO
Plan not required
Is the Data and Safety Monitoring Plan Acceptable?
• Entity responsible for monitoring is identified? and
• Policies and procedures for adverse event reporting are described? and
• Plan is appropriate with respect to risks to participants, complexity of study design, and methods for data analysis?
Regulatory bodies requires a Data and Safety Monitoring Board for multi-site clinical trials of interventions with potential risk to
participants.
YES
ABSENT
NO
No Information
ACCEPTABLE
Explain why the data and safety
monitoring plan is scientifically
acceptable.
UNACCEPTABLE
Contact
Scientific Review Administrator
UNACCEPTABLE
Negative impact on score.
Explain why the data and safety
monitoring plan is scientifically
unacceptable.
87
Safety Monitoring in Clinical Trials
88
Definitions
• Data Safety Monitoring
Plan (DSMP)
– Describes how the
study investigators plan
to oversee research
subject safety and how
adverse events will be
characterized and
reported
– The intensity and
frequency of monitoring
should be tailored to fit
the expected risk level,
complexity, and size of
the particular study
• Data and Safety
Monitoring Board
(DSMB/DMC)
– A group of individuals
with pertinent expertise
that review on a regular
basis accumulating data
from ongoing an clinical
trial
– Advises sponsor
regarding safety of
current and future
participants and validity
and scientific merit of the
trial
89
Study Risk Definitions
Minimal-risk:
Non-therapeutic trials such as survey research, questionnaires, blood samples,
or observations.
One standard definition is: A study where the magnitude of harm or discomfort is
not greater than that encountered in daily life or the performance of routine
physical or psychological examinations or tests.
Moderate-risk:
Phase II or phase III multi-intuitional industry sponsored trials with independent
data monitoring
High-risk:
Clinical trials with investigational agents, phase I clinical protocols, investigator
initiated INDs, manufacturing of product on campus, some phase II clinical
trials, and investigator initiated phase III clinical trials.
90
Which Studies Require
DSMB?
Clinical Research?
Yes
No
Phase III or Multicenter
Yes
No
Blinded, high-risk intervention, or
vulnerable population?
Yes
IRB + DSMP + DSMB
No
IRB + DSMP
91
DSMB Checklist
Preliminary DSMP Checklist
1)
2)
3)
4)
5)
6)
7)
8)
Is some form of study risk assessment?
Is there a description of the anticipated adverse events?
Is there a description of how adverse events will be
detected and monitored at a research subject level?
Is there an adverse event grading and attribution scale
described?
Is there a plan for the reporting of adverse events?
Is there a plan for annual reporting of adverse events?
Is there a description of who will be performing safety
reviews for the study and how often these will be
reviewed?
Has preliminary criteria for decision making regarding
continuation, modification or termination of the clinical
study been documented
92
Regulatory reports
•
•
•
•
•
15-Day NDA Report
CIOMS 1 Report
NDA Periodic Report
IND Annual report
Periodic Safety Update Report (PSUR)
• Med watch report
93
15-Day NDA Report
• Non-clinical study cases for a marketed
product and clinical study cases for an
investigation product with an active NDA
• AE- serious, unexpected and related
• Reference Labeling document
• Due date: 15 calendar day from the
company receipt date
• Submitted to US FDA
94
CIOMS-1 Report
• Council for International Organizations of
Medical Sciences
• AE = Serious and Related
• Reference labeling document: Not applicable
• Due date: 12 calendar days from company
receipt date
• For licensed product report has to be generated
to the respected company in the stipulated time
95
NDA Periodic report
• Required for all FDA-approved marketed
drugs
• Includes a compilation of all non-15 day
AE reports that have occurred in the US
and a listing of 15-day submitted reports
• Due date: Quarterly for the 1st 3 yrs
following date of FDA approval of an NDA
and annually thereafter
• Submitted to USFDA
96
IND Annual Report
• Required for all drugs for which an IND
has been opened
• Due date : 60 days following the effective
anniversary date
• Submitted to the US FDA
97
Periodic safety update report
(PSUR)
•
•
1.
2.
3.
4.
5.
The PSUR is a practical mechanism for summarizing
interval safety data covering short periods of time and
for conducting and overall safety evaluation
Includes
All serious, non clinical trial cases from a HCP
All Nonserious, non clinical trial cases with unlisted
AEs from a HCP
Clinical trial cases with a casual relationship with the
study drug
All solicited cases from a HCP with a casual
relationship with the subject drug
HCP EIU cases
98
LEGISLATIVE REPORTING
REQUIREMENTS
To the Sponsor, MHRA (Medicines and
Healthcare products Regulatory Agency),
Ethics Committee, all other investigators,
(must include a causality assessment):
• Fatal life/threatening SUSARs = within 7
days.
• All other SUSARs = No later than 15
calendar days.
99
SIGNAL DETECTION
100
Data assessment in Pharmacovigilance
•
•
•
•
•
•
Individual case report assessment
Aggregated assessment and
interpretation
Signal detection
Interactions and risk factors
Serial (clinicopathological) study
Frequency estimation
101
Signal Detection
• “An alert from any available source that a drug may be
associated with a previously unrecognized hazard or that
a known hazard may be quantitatively (more frequent) or
qualitatively (e.g., more serious) different from existing
expectations”
• Minimum requirement: Single, well documented report
with a positive rechallenge or replication of findings in a
series of reports
SNIP Rule for signals:
»
»
»
»
Wish to examine signals that are:
Strong
New
Important
Preventable
102
WHO-UMC definition of a signal
• Reported information on a possible causal
relationship between an adverse event and a
drug, the relationship being unknown or
incompletely documented previously.
Usually more than a single report is required
to generate a signal, depending upon the
seriousness of the event and the quality of
the information.
• Edwards IR, BiriellC. Drug Safety 1994;10:93102
103
A signal consists of
• Hypothesis
• Data
• Arguments, in favor or against
104
Data of a signal
• Qualitative (clinical)
• Quantitative (epidemiological)
• Experimental’
• Develops over time
105
1. Signal detection
•
Selection of a possibly relevant association
(hypothesis generation)
•
Preliminary assessment of the available evidence
(signal strengthening)
2. Signal follow-up
106
Criteria for selecting a signal
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Unknown adverse reaction
Unexpected
Expected but ‘unlabelled’
Strong statistical connection
Low background frequency
Specific, characteristic
Objective (definitive) event
Typically drug-related event or Critical Term
Serious
High potential relevance
Known (and labelled)
Weak statistical connection
High background frequency
Unspecific, trivial event
Subjective event
Common disorder, e.g. infectious or ‘endogenous’
Not serious
Low relevance
107
When is a signal likely to be
relevant?
•
•
•
•
•
•
•
•
•
Early Warning
New adverse reaction; new drug
Public health perspective
Important drug (serious indication; widely used)
Serious reaction
Large number of cases; rapid increase in reporting
Regulatory intervention (prevention)
Change in benefit/risk
Scientific or educational value
108
Signal follow-up (same database)
• Drug exposure
• Development over time of the quantitative
data and the consistency of the pattern
• Signal strengthening
–individual case report assessment
–reporting distribution
–‘best case-worst case’scenario
–targeted comparisons
–nested case control studies
109
Signal follow-up (other sources)
• Similar connection in other countries
• WHO-UMC international database,
• Additional observations (e.g. literature,
registration file, other databases)
• Experimental data (e.g.
pharmacological, immunological)
110
The balance of evidence in a signal
Quantitative strength of the association
–number of case reports
–statistical disproportionality
–drug exposure
• Consistency of the data (pattern)
• Exposure-response relationship
–site, timing, dose, reversibility
• Biological plausibility of hypothesis
–pharmacological, pathological
• Experimental findings
–e.g. dechallenge, rechallenge, blood levels, metabolites,
drugdependentantibodies
• Analogies
• Nature and quality of the data
–objectivity, documentation, causality assessment
111
From signal to action
• Internal communication (national
centers, UMC, company, academia)
• Initiation of further study (signal testing)
• Regulatory action (e.g. data sheet
change)
• External communication (drug
information centers, national drug
bulletin, publications)
112
Signal detection using a neural
network approach
• If the Posterior probability > Prior
probability
– The drug ADR combination is present more
often than expected
– This is represented by a high value of
Information Component (IC)
– IC=log2 (Posterior Probability/ Prior
Probability)
113
Automated quantitative signal detection
• Extremely large numbers ofdrug adverse reaction combinations
• Selects automatically high-interest
combinations, using quantitative
disproportionality
• Manageable subsets of data
• No human time needed
• No investigators bias
• Objective, transparent, reproducible
• Flexible / adjustable
• Explorative
114
Signal Detection at the
Uppsala Monitoring Centre
Eur J Clin Pharmacol 1998;54:315-321
•
•
•
A combination of automated quantitative
data mining, using Bayesian statistics and
a neural network architecture (Information
Component – ‘IC value’)
‘Triage’
Human assessment
– National Centres
– Review Panel
– UMC staff
115
The SIGNAL document
• Sent to all National
Centres (national
distribution)
• Individualized
section available to
industry
• All recipients
encouraged to
comment on topics
presented
116
Statistical analysis
• Allows pattern recognition in large
amounts of data
• Also incomplete case data of value
• Allows identificaion of interactions and
syndromes
117
Risk Benefit Analysis
• Risk-benefit analysis is the
comparison of the risk of a situation to
its related benefits
• For research that involves more than
minimal risk of harm to the subjects,
the investigator must assure that the
amount of benefit clearly outweighs the
amount of risk
• Only if there is favorable risk benefit
ratio, a study may be considered
ethical
• The Helsinki Declaration [1] and the
CONSORT statement [2] stress a
favorable risk benefit ratio
• Risk must include: Physical – death,
disability; Psychological – depression
and anxiety; Social
– discrimination; Economical –
job less
118
Benefit/risk evaluation
Edit product information:
•
•
•
•
•
•
•
•
Indications/use
Dosing instructions
Contra-indications
Interactions
Pregnancy/lactation
Warnings/precautions
Undesirable effects
Over dosage
Withdraw marketing
authorisation
119
120
121
122
123
124
Regulatory Bodies
125
WHO Collaborating Centre for
International Drug Monitoring
The Uppsala Monitoring Centre
Stora Torget 3, 75320 Uppsala, Sweden
www.who-umc.org
126
The Uppsala Monitoring Centre
• 1968 - WHO Collaborating Centre for
International Drug Monitoring, Geneva
• 1978 - Moved to Uppsala after agreement
between Sweden and WHO
• Non-profit foundation with international
administrative board
• WHO Headquarters responsible for policy
• Self-financing
• Global pharmacovigilance
• Around 100 national Pharmaco-vigilance
Centers around the world
127
128
Pharmacovigilance regulations
• Medicines for Human Use Clinical Trials
Regulations 2004 - legal requirements
• EU directive and detailed guidance
required harmonisation of laws- some
flexibility
• Internationally accepted principles of good
clinical/trial practice, data management,
reporting E3, E6, E8, E2A
129
Pharmacovigilance in practice
• All protocols must have a PV section
• Risk to patients varies in the range of clinical trials.
Extent of recording and notification of adverse events
may vary depending on knowledge of the risks and
benefits of drugs under study and aims of the trial.
• Responsibilities and systems to deal with recording,
assessment and reporting must be clearly stated.
• Time frames for notification, assessment and reporting
are critical
• As are SOPs
130
ICH Topics relevant to
Pharmacovigilance
E2, Clinical Safety
•
E2A, Definitions and Standards for
Expedited Reporting
E2B, Data Elements for
•
Transmission of ADR
reports
E2C, Periodic Safety Update
•
Reports
E2E, Pharmacovigilance planning
•
131
ICH Topics relevant to
Pharmacovigilance
• M1, Medical Terminology (MedDRA)
• M2, Electronic Standards for the Transfer
and Data
of Regulatory
Information
(ESTRI)
• M5, Data Elements and Standards
for Drug Dictionaries
132
E2E-Pharmacovigilance planning
• Pharmacovigilance Specification
is a summary of the:
–Important identified risks,
–Important potential risks, and
–Important missing information about
a product.
133
Concept of E2E Guideline
Clinical Trials
Available
Data/information
NDA
Approval
Review
Product
Launch
On the Market
Pharmacovigilance
Specification
Pharmacovigilance
Activities
Pharmacovigilance
Plan
134
Pharmacovigilance and India
• India has become a major hub for clinical trials.
However, whether patients in India receive safe
drugs or not is still very much in question
• India's Drugs Control Department within the
Ministry of Health & Family Welfare initiated the
establishment of a nationwide network to build a
comprehensive Pharmacovigilance data system
in 2004; Different PV regional centers have been
listed in the below site.
http://www.pharmacovigilance.co.in/home.html
135
National PVG Programme
National Parmacovigilance Center:
Office of the Drugs Controller General of
India
Central Drugs Standard Control Organization,
(Directorate General of Health Services),
Ministry of Health & Family Welfare
Government of India
National
PVig
Center
Zonal Center 1: for North and
Zonal Center 2: for West and
South Regions
East Regions
NE
Zonal
N
Regional
E
Regional
SW
Zonal
W
Regional
S
Regional
136
Where to report
Local ADR Reporting Centre
Peripheral Pharmacovigilance Centre
Zonal Pharmacovigilance Centre – Statistical
Regional Pharmacovigilance Centre – Causality
Central Drug Standardization Control Organization
The International Pharmacovigilance Database managed by WHOUPPSALA monitoring Centre in Sweden
137
Pharmacoepidemiology
•
•
Study of the use and effects of drugs in large groups of people
Pharmacoepidemiology benefits from the methodology
developed in general epidemiology and may further develop
them for applications of such methodology unique to
Pharmacoepidemiology.
Epidemiology can be defined as the study of the distribution
and determinants of diseases in populations. Epidemiological
studies can be divided into two main types:
•
–
Descriptive epidemiology describes disease and/or exposure and
may consist of calculating rates, e.g., incidence and prevalence.
Such descriptive studies do not use control groups and can only
generate hypotheses, not test them. Studies of drug use would
generally fall under descriptive studies.
Analytic epidemiology includes two types of studies:
– observational studies, such as case-control and cohort studies,
and
– experimental studies which would include clinical trials such as
randomised clinical trials. The analytic studies compare an exposed
group with a control group and are usually designed as hypothesis
testing studies
138
Infrastructure requirements in practicing Pharmacovigilance
and Pharmacoepidemiology
•Good pharmacovigilance practice is based on
acquiring complete data from spontaneous adverse
event reports, also known as case reports. The reports
are used to develop case series for interpretation.
•Effective pharmacovigilance is dependent on the
availability of information on the clinical effects of
medicines in representative populations, as used in
normal practice. For this to happen, it requires a
robust pharmacovigilance system, which includes a
system of collecting and monitoring suspected ADRs
and processes for reviewing the data to decide
whether further investigations are necessary.
139
AE Case Processing
AE Reporting Forms
• AEM Form: ADVERSE EVENT MONITORING
(REPORT)
AEM Form
Adobe Acrobat 7.0
Document
• CIOMS Form
Adobe Acrobat 7.0
Document
• Medwatch Form
Microsoft Word
Document
Adobe Acrobat 7.0
Document
Action Taken with Drug
• Action Taken with Drug:
– Withdrawn (Temporarily/Permanent)
– Dose reduced
– Dose increased
– Dose not changed
– Post therapy
– Unknown
– Not applicable
• ICH E2B (R3)
Dechallenge - Rechallenge Definitions
• Dechallenge – withdrawing the drug(s)
and recording the outcome – improved or
not improved
• Rechallenge – giving one drug again
under the same conditions as before and
recording the outcome – recurrence or no
recurrence.
Dechallenge
Dechallenge = withdrawal of drug
“Positive” dechallenge = improvement of reaction
when dechallenge occurs. Resolution of suspected
ADR when the drug is withdrawn is a strong,
although not conclusive indication of drug-induced
reaction.
Rechallenge
Rechallenge: Reintroducing the drug after a dechallenge
•Positive rechallenge (symptoms re-occurring on readministration)
•negative rechallenge (failure of a symptom to re-occur after
re-administration)
•Rechallenge is only justifiable when the benefit of reintroducing the drug to the patient outweighs the risk of
recurrence of the reaction. This is rare. In some cases the
reaction may be more severe on repeated exposure.
Rechallenge therefore requires serious ethical
considerations.
Outcome
• Outcome of reaction/event at the time of last
observation
–
–
–
–
–
–
Recovered/resolved
Recovering/resolving
Not recovered/not resolved
Recovered/resolved with sequelae
Fatal
Unknown
–
–
–
–
Remains in Study
Withdrawn
Lost to follow-up
Death
• Outcome of subject in study
147
Case 1
A 42-year-old female experienced vomiting
during treatment with 200mcg Pulmicort at
night by inhalation for her asthma. The onset
of the reaction was on 3rd August 2006 until
5th August 2006. She been prescribed this
drug since end of July. The drug was
stopped on the 5th of August and patient
recovered. No rechallenge performed and her
doctor change the drug.
Case 2
• A 68-year-old male patient was started with
Crestor on the 29th Jan. 2007 for his
hyperlipidaemia. On the 2nd of Feb. 07,
patient felt very ill. Upon admission, the
diagnosis was myositis and abnormal
hepatic function (ALT: 100 units/ml). Patient
also took Sandimmun Neoral for his bone –
marrow transplant rejection since October
2006. Crestor was discontinued and patient
recovered a few days later. No rechallenge
been performed.
Case 3
• A 67-year-old woman reported , whose medical history included
diabetes mellitus, hypertension and also been diagnose with
Alzheimer’s Disease. This woman been on long term treatment of
Amlodipine 5mg/daily, Metformin 1gm/bd and Glibenclamide 5mg/bd.
She started receiving daily oral Exelon® (Rivastigmine) 6mg daily.
After 5 months she was hospitalised for dizziness and syncope. On
admission her BP was 90/60mm Hg, her pulse rate was 34 beats/min,
and complete heart block was evident on 12 lead ECG.
• The woman received a temporary transvenous pacemaker, and
Exelon® and amlodipine was discontinued. Angiography showed
normal coronary anatomy. After 3 days admission her heart block
spontaneously resolved and sinus rhythm was restored.
• Oral Exelon® was restarted that day, and complete heart block
recurred on day 4. the woman received a VVI permanent pacemaker
the following day. Amlodipine was restarted and Exelon® was
continued at the same dosage. She had not experienced further
syncopic episodes or dizziness at follow up 3 months later.