Transcript www.alphapharma.eu

Pharmacovigilance
Clinical Pharmacology Seminar
Department of Pharmacology and Toxicology,
Faculty of Pharmacy
Vladimir Patras, PharmD, MBA
Withdrawn Drugs (in the US, since 2000)
Drug
Lumiracoxib
Aprotinin
Tegaserod
Ximelagatran
Valdecoxib
Pemoline
Rofecoxib
Levomethadyl
Rapacuronium
Cerivastatin
Trovafloxacin
Amineptine
Cisapride
Troglitazone


Year
2008
2008
2007
2006
2005
2005
2004
2003
2001
2001
2001
2000
2000
2000
Reason
Hepatotoxicity
Kidney and cardiovascular toxicity
Cardiovascular ischemic events
Hepatotoxicity
Dermatology adverse events
Hepatotoxicity
Thrombotic cardiovascular events
Fatal Arrhytmia
Risk of fatal bronchospasm
Rhabdomyolosis
Hepatotoxicity
Hepatotoxicity, dermatological side effects, abuse potential
Cardiac arrhythmias
Hepatotoxicity
Other drugs were restricted in use to exclude some patient populations or
indications - Alosetron
Some drugs were withdrawned and reintroduced after further studies or
special safety measures – Natalizumab withdrawn in 2005 and reintroduced
in 2006
Do you know ?




Number of deaths resulting from medical errors in the
US may be 100 000 per year.
Medical errors are among leading causes of death
(4th - 6th) – more prevalent then motor vehicle
accidents. 5 % of all deaths may be caused by
pharmaceuticals.
Medical errors lead to excess costs ($ 37 B/year in the
US), health injury
Medical errors are preventable in large scale (at least
in 50 %) but in some cases new approaches are
needed
It should be recognized



Each drug has its side effects
Pharmacological/toxic effect frontier is only
defined by dose quantity and may differ from
patient to patient. Theoretically each drug can
be toxic.
There are efficient mechanisms how to tackle
both expected and unexpected adverse drug
reactions. Medicines safety is principal task of
regulatory agencies.
What is Pharmacovigilance ?




Data gathering related to the detection, assessment,
understanding, and prevention of adverse events
Identifying new information about hazards associated
with medicines, preventing harm to patients
Post-marketing surveillance (?)
Medical errors are broader category which includes
adverse reactions but also other factors (diagnostic
errors, equipment failure, nosocomial infections ... )
Terms



Adverse Event (AE) – any untoward medical
occurrence that may present during treatment with a
pharmaceutical product but which does not
necessarily have a casual relationship with this
treatment
Adverse Drug Reaction (ADR) – a response to a drug
which is noxious and unintended, and which occurs at
doses normally used in man.
Serious Adverse Event (SAE) – AE that is either lifethreatening, fatal, cause of prolong hospital admission,
cause persistent disability or concern misuse or
dependence
Terms


Serious Adverse Drug Reaction (SADR) – ADR where
SAE conditions of severity applies
Unexpected Adverse Drug Reaction (UADR) – an
adverse reaction, the nature or severity of which is not
consistent with market authorization, or expected from
the characteristics of the drug.
Terms

Signal – reported information on a possible
relationship between an adverse event and a
drug, 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
Expected and Unexpected Events



Expected are those adverse events that were observed during clinical trials
or post-approval observations and are mentioned in Summary of Product
Characteristics (SPC)
Unexpected are those adverse events that were not previously observed and
are not documented (in SPC)
Based on frequency of occurrence there are following categories of adverse
events:
Category
Very common
Common
Uncommon
Rare
Very rare
Frequency
≥ 1/10
≥1/100 and <1/10
≥ 1/1,000 and <1/100
≥ 1/10,000 and <1/1,000
< 1/10,000
Avandia (Rosiglitazone) Adverse Reactions - SPC
Types of Adverse Reactions (Rawlins and
Thompson Classification)
Type A Effects (“Augmented”)




Due to pharmacological effects
Are dose related – may often be avoided by
using doses which are appropriate to the
individual patient
Are common, can be experimentally
reproduced, known before marketing
Example: hypnotic effect after H2
antihistaminics
Types of Adverse Reactions (Rawlins and
Thompson Classification)
Type B Effects (“Bizzard”, idiosyncratic reactions)




Generally rare and unpredictable
Little or no dose relationship, not related to drug
pharmacodynamics
Occur in predisposed, intolerant patients – can
be explained by rare genetic polymorphism,
allergic reactions
Example: Penicilline allergies
Types of Adverse Reactions (Rawlins and
Thompson Classification)
Type C Effects (“Continuous”)



Adverse reactions after long term therapy
There is often no suggestive time relationship
and the connection may be very difficult to
prove. The use of a drug increases the
frequency of “spontaneous” disease
Example: carcinogenesis
Types of Adverse Reactions (Rawlins and
Thompson Classification)
Type D Effects (“Delayed”)


Adverse effect may be presented years after a
drug was used
Example: Vagina cancer of daughters when
their mother was treated by diethylstilbestrol
Type E Effects (“Ending”)


Absence of drug after withdrawal – rebound
effect
Example: corticosteroids in asthma treatment
Causality Assessment
To determine likelihood of a causal relationship
between drug exposure and adverse events it is
necessary to evaluate

Association in time/place between drug use and
event

Pharmacology (including current knowledge of
nature and frequency of adverse reactions)

Medical or pharmacological plausibility (signs and
symptoms, tests, pathological findings, mechanism)

Likelihood or exclusion of other causes
(Case reports describe suspected ADRs)
Causality Assessment

There are more assessment scales for causality evaluation which include:

Karch and Lasagna scale

Naranjo scale

WHO probability scale

Jones scale
Karch and Lasagna

Uses three categories of causality

A – causality is highly probable

B – not adequate proof of causality

0 – data are not adequate to assess causality
Causality Assessment
NA RANJO's ALGORITHM
question
Yes
No
Don't know
Are there previous conclusion reports on this reaction?
+1
0
0
Did the adverse event appear after the suspect drug was administered?
+2
-1
0
Did the AR improve when the drug was discontinued or a specific
antagonist was administered?
+1
0
0
Did the AR reappear when drug was readministered?
+2
-1
0
Are there alternate causes [other than the drug] that could solely have
caused the reaction?
-1
+2
0
Did the reaction reappear when a placebo was given?
-1
+1
0
Was the drug detected in the blood [or other fluids] in a concentration
know n to be toxic?
+1
0
0
Was the reaction more severe when the dose was increased, or less
severe when the dose was decreased?
+1
0
0
Did the patient have a similar reaction to the same or similar drugs in any
previous exposure?
+1
0
0
Was the adverse event confirmed by objective evidence?
+1
0
0
Classification of Adverse Events
based on its severity



Mild – no changes in therapy are needed
Moderate – change of therapy is desired but the
events are not life-threatening or causing
disability
Serious – is either life-threatening, fatal, cause
of prolong hospital admission, cause persistent
disability
Pharmacology in Adverse Reactions





Detailed safety profile of a drug can only be evaluated and described on
base of clinical research and postmarketing surveillance
However, there are some factors that can be associated with higher safety
risks. These risk can be on side of:

Administered drug

Patient

Environment (xenobiotics, physical conditions)
Higher safety risks are associated with medicines with no specific
mechanism of action such as neuroleptics (haloperidol, chlorpromazine),
non-selective cyclooxygenase inhibitors, cytostatics, morphine analgetics
Another group is medicines with narrow therapeutic range (i.e. low
therapeutic index) – cardiac glycosides, aminoglycoside antibiotics
(gentamycin), theophylline
Therapeutic index = Median Toxic Dose (TD50)/ Median Effective Dose
(ED50)
Risks dependent on Patient

Kidney insufficiency – failing excretion of drugs/active metabolites

Liver disease – failing drug metabolism





Polymorbidity – combination of factors such as drug interactions, multi-organ
injury
Immunocompetence – higher doses of some drugs (antibiotics) may be
needed in decreased immune response
New born age – drug metabolizing systems are not fully developed
Allergies – risk of drug allergies is higher in patients with already suffer from
another allergy
Some specific diseases – such as contraindication of beta blockers in
asthma
Pharmacogenetics



Study of how individual`s genetic inheritance affects response to drugs
Genetic polymorphisms in metabolizing enzymes can cause substantial
differences in drug response. Some polymorphisms are very rare
Genetic testing was developed to detect various polymorphisms in
metabolizing enzymes (CYP 450) – this opens possibility of personalized
prescribing to avoid adverse events
Important enzymes in drug metabolism with more known polymorphisms

Cytochrome P450 polymorphisms – influence metabolism of various drugs

Thiopurine Methyltransferase (TMT) – metabolism of thiopurines

Acetyltransferases
Another mechanism is interaction with Human Leukocyte Antigen system (HLA
) - klozapin, levamizol, carbamazepine
Risks dependent on Other Factors
Drug dependent

Drug interactions
Environment dependent

Xenobiotics (pesticides, veterinary antibiotics) can
interact with drugs metabolism, most commonly on
CYP 450 level
Classification of Adverse Events
Adverse events can be roughly classified on base of its underlying mechanism,
although this classification is not unambiguous and there are disputable
cases to which category an event can be attributed




Intolerance – lower then usual dose produce anticipated response
Idiosyncratic (“unusual”) response – determined by genetic alteration,
producing response that is not anticipated
Allergy – response modulated by immune system
Pseudoallergy – reaction similar to allergy but not mediated by immune
system
System of Safety Data Gathering
Clinical Trials
Healthcare
Professionals
Pre-Approval
Post-Approval
National Regulatory
Authority
Patients
Pharmaceutical
Companies
International Safety
Databases
New Drug Approval Process





Each new drug (New Chemical Entity,
NCE) shall prove its safety and efficacy
in order to gain marketing authorization
Scientific data on efficacy/safety are
collected in clinical trials
If a drug meets all safety (and efficacy)
requirements New Drug Application
(NDA) is submitted to regulatory agency
Regulatory agency reviews the
application, may require further studies.
It issues Marketing Authorization (MA) or
reject application, guided by risk/benefit
evaluation
Research of drug safety continues after
drug is introduced in clinical praxis as
post-marketing surveillance (phase IV
study)
Cerivastatin Case Study






Cerivastatin was developed by Bayer to compete with other statins.
Rhabdomyolysis cases were rare in other statins (3.3 per 100 000 patientyears).
Cerivastatin gained US marketing authorization in June 1997 as cholesterol
lowering agent and cardiovascular disease prevention. It was introduced to
US market in early 1998 under brand names Baycol and Lipobay.
Soon after (until May 1998) Bayer received 6 SADRs of cerivastatin
associated rhabdomyolysis in patients also taking gemfibrozil. This was
followed by label update – rhabdomyolysis warning.
First case of rhabdomyolysis associated with cerivastatin-gemfibrozil
combination published in April 1999.
July 1999 - Clinical trial of 1.6 mg cerivastatin reveals high incidence of
severe CK elevation (12 %) but the results are not published.
Gemfibrozil-cerivastatin coprescription is contraindicated in December 1999
Cerivastatin Case Study

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By 2000, 549 cases of rhabdomyolysis associated with cerivastatin use has
been reported to WHO Collaborating Centre in Uppsala
Higher risk compared to other statins was admitted by Bayer in March 2000
Label update of April 2001 stated 0.4 mg as starting dose (it became clear
that higher doses are associated with higher elevated CK levels)
That time Bayer performed study on the risk of myopathy. This study was
later criticized because of its poor design but results has not been published.
The final report was provided to the company in June 2001.
Bayer voluntarily withdraws cerivastatin worldwide on August 8th 2001
FDA publish research in 2002 which found mortality rates from
rhabdomyolysis for cerivastatin users were 16 to 86 times higher than those
of other statins. However, rhabdomyolysis asscociated with cerivastatin was
found to be 270 cases per 100 000 patient-years (most cases were not fatal)
in patients taking 0.4 mg cerivastatin.
Bayer faced approx. 8000 lawsuits in connection to Baycol/Lipobay
Who Regulates Drug Safety




Slovakia – State Institute for Drug Control, Section of
Drug Safety and Clinical Trials
Czech Republic - State Institute for Drug Control,
Pharmacovigilence department
UK – Medicines and Healthcare Products Regulatory
Agency, Vigilence Risk Management of Medicines
USA – Food and Drug Administration, Center for Drug
Evaluation and Research
International Cooperation in Drug
Safety


EudraVigilence – data processing network for
reporting and evaluating suspected adverse reactions
of medicinal products in European Economic Area
WHO Monitoring Centre in Uppsala

Established in 1978

Coordination of the WHO programme for
International Drug Monitoring

Collection, processing of data, Education, Research
Sources of Information on Drug Safety

Pre-clinical studies

Clinical trials (pre- and post-marketing)

Spontaneous adverse reaction reporting

Epidemiological studies

Data collected for other purposes

Routine statistics

Databases of prescription and outcomes
Pre-clinical Studies
Standard toxicology pre-clinical tests are:

Acute toxicity

Repeat use toxicity

Local irritation tests

Pyrogenity

Reproductive toxicity

Mutagenity

Carcinogenity
Clinical Trials




Principal aim of clinical is to collect safety (and efficacy) data.
The investigational drug shall prove safety profile consistent
with human testing on base of pre-clinical studies. Clinical trials
are subject of regulatory approval.
The sponsor shall keep detailed records of all adverse events
and he shall submit these records on request of regulatory
authority.
The sponsor shall ensure that all relevant information about
suspected serious unexpected adverse reactions have to be
recorded and reported to regulatory authority
Other investigators participating in multicentric trials shall also
be informed on serious unexpected adverse events
Clinical Trials




Safety profile of investigational drug is described in
Investigator`s Brochure (likewise SPC in marketed drugs
Procedures for reporting of adverse events in clinical trials
slightly differ from post-approval reporting. Standard are CIOMS
forms, electronic reporting is now preferred
Detailed guidance on the collection, verification and
presentation of adverse reactions reports arising from clinical
trials on medicinal products for human use, European
Commission, April 2006
Serious events such as deaths are relatively rare and may
present reason for termination of a clinical trial
Rationale for Post-Marketing Surveillance





Tests in animals are insufficiency predictive of human
safety
In clinical trials patients are selected and limited in
number
Conditions of use in trials differ from those in clinical
practice
Duration of trials is limited
Information about rare but serious adverse reactions,
chronic toxicity, use in special groups such as children,
the elderly or pregnant woman or drug interactions is
often not available
Who Should Report Safety Data

Physicians

Pharmacists


Pharmaceutical companies qualified persons –
(Pharmacovigilence/Regulatory manager)

Investigational products (clinical trials)

Post-approval reporting – Individual Case Safety
Report (ICSR), Periodic Safety Update Report
(PSUR)
In many countries patients are encouraged (but
not obligated) to report side effects
What to Report – WHO recommendations



Every single problem related to the use of a drug, because
probably nobody else is collecting such information
All suspected adverse reactions
ADRs associated with radiology contrast media, vaccines,
diagnostics, drugs used in traditional medicine, herbal
remedies, cosmetics, medical devices and equipment

Lack of efficacy and suspected pharmaceutical defects

Counterfeit pharmaceuticals

Development of resistance
What to Report (at least)






Requirements for reporting differ from country to country. However, in
each developed country healthcare professionals are legally
obligated to report adverse reactions (although it is not always clearly
stated which)
It is important to report serious unexpected ADRs – those that are not
described in SPC. Unexpected include also side effects mentioned in
SPC when these occur in higher frequencies then described.
Most cases of unexpected ADRs are associated with medicines
newly introduced on the market
It has no sense to report expected adverse
In clinical praxis it is usually not easy to evaluate causality – report
also in cases you are not sure about causal relationship
Heathcare professionals may report adverse events also to marketing
authorization holder for a medicine but are not obligated to
How to Report - Slovakia
SPRÁVA O NEŽIADUCOM ÚČINKU LIEKU
Dátum nar.:
Iniciálky pacienta::


Guidance No. 15/2004 on reporting
of side effects of registered
medicines
Form downloadable from SIDC site
http://www.sukl.sk
1................................…...................................•
4..................................................................•
2......................................................................•
5..................................................................•
3......................................................................•
6..................................................................•
Vznikla reakcia u
hospitalizovaného
pacienta?
áno - nie
hospitalizácia pre
NÚL?
o predĺženie hospitalizácie?
bol ohrozený život
pacienta?
o trvalé poškodenie pacienta?
umrel pacient?
Dátum úmrtia:
Podozrivý liek:

Heathcare professional are
obligated to report suspected
adverse drug reactions with
presumed casual relationship
Sex: muž - žena
Dátum nežiaducej reakcie:..................................................
Nežiaduce reakcie:
Príčina smrti:
Podanie
Dávka
od - do
Diagnóza
1
Ostatné
lieky
2
3
4
5
6

In 2004 there were about 900
reports mostly from physicians.
Number of reports is significantly
lower compared to other EU
countries
7
8
9
Prestal sa liek podávať?
áno-nie
Upravila sa reakcia po vynechaní lieku ?
áno- nie- neviem
Objavila sa reakcia po novom podaní ?
áno- nie- neviem- nepodal sa
Používal pacient liek v minulosti?
áno - nie - neviem
Anamnéza: o NÚL na lieky?
Aké ?
o alergia?
Je správa z klinickej skúšky?
Odbornosť lekára:
Meno lekára:
áno - nie
o fajčenie?
o tehotenstvo? o alkohol, drogy
z epidemiol. štúdie?
áno - nie
nemocničný lekár?
áno - nie
Adresa zariadenia:
How to Report - UK






“YellowCard Scheme” - established in 1964
MHRA operates site
http://yellowcard.mhra.gov.uk/
for reporting of adverse drug reactions
Reporting by post is also possible
Both patients and healthcare professionals
are encouraged to report all suspected
adverse drug reaction. MHRA evaluates
whether risk is serious and whether there
is a causality.
Pharmacies are encouraged to display poster on YellowCard and mention it
to patients who may experience ADRs when giving advice
MHRA provides yellow card to patients (distributed also thru pharmacies)
with information on reporting. Pharmacists are considered to be crucial in
informing patients on ADRs reporting
Content of Report (MHRA recommendations)

The symptoms or a description of a side effect
Information about the person who experienced
the side effect (as a minimum, their initials, sex,
and age at the time of side effect)

The name of the medicine(s) thought to have
caused the side effect

The name and full address of the reporter so that
the report can be acknowledged and contact
made for further information, if neccessary.

Reporting Requirements for Marketing Authorization
Holders (Pharmaceutical Companies)



The Marketing Authorization Holder (MAH) should ensure that h has an
appropriate system of pharmacovigilance in place in order to assume
responsibility and liability for his products on the market and to ensure that
appropriate action may be taken when necessary. MAH should therefore
ensure that all information relevant to the risk-benefit balance of a medicinal
product is reported to the Competent (Regulatory) Authorities and European
Medicines Agency fully and promptly in accordance with the legislation
Qualified Person Responsible for Pharmacovigilance
MAH submit Periodic Safety Update Report (PSUR) for drugs marketed for
less than five years.

Submitted in 6 months intervals after MA, once per year two years after
MA, then 3-yearly intervals or upon request of regulatory authority

Presentation, analysis and evaluation of new or changing safety data

Sources of data include: spontaneous reports, scientific literature,
warning received from other regulatory authorities worldwide, data from
special registries, poison control centers and others
Safety Data Access


http://www.mhra.gov.uk/Safetyinformation/index.htm
MHRA publish detailed report
for most of registered drugs
summarizing nature of
adverse events
Regulatory Actions

Safety warnings

Labeling change/changes in SPC

Withdrawal
Special Cases for Pharmacovigilence

Some groups of medicinal products are not required to document their safety
– natural medicines, homeopathic preparations
Natural (herbal) medicines

Exact composition is often not known, efficacy nor safety is usually not
documented

Marketing Authorization is granted on base of “traditional use”

37 ADR reports in Australia related to Echinacea use in allergy
Homeopathic preparations


Zycam Cold Remedy case – unusual dilution resulted in permanent loss of
smell in several subjects and 340 filed and settled lawsuits
Content of alcohol in some preparations for children is higher than allowed in
allopathic medicines
Special Cases for Pharmacovigilence



Medical Devices – regulated by State Institute for Drug Control.
Slightly different reporting requirements – in competence of
Medical devices department, particular reporting guidance
Veterinary products – competent (regulatory) authority in
Slovakia is Institute for State Control of Veterinary Biologicals
and Medicaments based in Nitra. Veterinary legislation and
marketing requirements are in many aspects similar to human
medicines. EMEA is competent authority for veterinary products
on European level.
Nutritional Supplements – are considered to be special purpose
nutrients. Basic safety but not efficacy proof is required for
marketing authorization. Regulated in Slovakia by National
Health Authority of the Slovak Republic (NHA SR). NHA SR
regulates also cosmetic products
Disputable and Unresolved Issues



Regulatory agencies are now under much more public
attention then they used to be ~10 years ago. Affairs such
as Vioxx, Lipobay withdrawals attracted public attention
and FDA criticism. FDA approach is considered to be more
cautious now
More stringent approach of regulatory bodies has not
always been welcomed – there are claims that absence of
some unapproved medicines on the market caused more
harm then would be caused by its side effects
Some countries lack recourses to establish
pharmacovigilance systems. WHO provides some
assistance in establishing pharmacovigilance systems in
developing countries
How to Deal with Expected Adverse
Reactions and Medical Errors




Focus on medical errors has increased in
recent
Complex solutions and system approach
New concepts of quality management in
healthcare – application of knowledge from
other industries
It is expected that most errors are on level of
diagnosis/prescribing and only about 15 % in
dispensing of medicines
Potential Sources of Errors in
Pharmaceutical Care



Handwriting of prescriptions
Prescribing doctors missing information on other
prescriptions for a patient (drug interactions)
Similar-sounding and look-alike names and packages of
medication

Level of stress on workplace

Unclear records in information system

Bad system of stock alignment/organization

Disruptions in information availability and flow
Solutions

It is expected that 50 – 75 % of medical errors are preventable

Introduction of advanced medical information systems

Electronic Health Record (EHR)

Automatic checks for dose, interactions, allergies, resistance

Personalized prescription (on base of pharmacogenetic
data)

Written procedures, quality management and safety audits

Analyze all errors, research what enabled them

Try to design uncomplicated processes
Personal responsibility (?)
Trial with Zheng Xiaoyu, former director of State Food and Drug Administration
of China, Beijing Intermediate Court, May 29, 2007
Zheng Xiaoyu was convinced of taking bribes for enabling approval of unsafe
medicinal products. He was executed on July 10, 2007
Where to find information


Monographies/Compendia

Davies: Textbook of adverse effects

Dukes: Meyler`s side effects of drugs
Journals


Newsletters


Regulatory Toxicology and Pharmacology
Drug Safety Update – published by MHRA
Regulatory Agencies

FDA: http://www.fda.gov/

EMEA: http://www.emea.europa.eu/

SIDC: http://www.sukl.sk
Thank You For Your Attention !


This presentation is published at
http://vpatras.blogspot.com
You will find learning article on
pharmacovigilance summarizing this seminar at
the same site