This document discusses pharmacovigilance and drug safety. It provides examples of drugs that have been withdrawn from the market in the US since 2000 due to safety issues like hepatotoxicity and cardiovascular toxicity. It also discusses key terms related to adverse drug reactions and how causality is assessed. Pharmacovigilance aims to identify safety issues with medicines through post-marketing surveillance.

1. Pharmacovigilance
Clinical Pharmacology Seminar
Department of Pharmacology and Toxicology,
Faculty of Pharmacy, Comenius University
Nov 2009
Vladimir Patras, PharmD, MBA

2. Withdrawn Drugs (in the US, since 2000)
Drug Year Reason
Lumiracoxib 2008 Hepatotoxicity
Aprotinin 2008 Kidney and cardiovascular toxicity
Tegaserod 2007 Cardiovascular ischemic events
Ximelagatran 2006 Hepatotoxicity
Valdecoxib 2005 Dermatology adverse events
Pemoline 2005 Hepatotoxicity
Rofecoxib 2004 Thrombotic cardiovascular events
Levomethadyl 2003 Fatal Arrhytmia
Rapacuronium 2001 Risk of fatal bronchospasm
Cerivastatin 2001 Rhabdomyolosis
Trovafloxacin 2001 Hepatotoxicity
Amineptine 2000 Hepatotoxicity, dermatological side effects, abuse potential
Cisapride 2000 Cardiac arrhythmias
Troglitazone 2000 Hepatotoxicity

Other drugs were restricted in use to exclude some patient populations or
indications - Alosetron

Some drugs were withdrawn and reintroduced after further studies or special
safety measures – Natalizumab withdrawn in 2005 and reintroduced in 2006

3. 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

4. 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.

5. 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 ... )

6. 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 life-
threatening, fatal, cause of prolong hospital admission,
cause persistent disability or concern misuse or
dependence

7. 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.

8. 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

9. Expected and Unexpected Adverse
Reactions

Expected are those adverse reactions 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 Frequency
Very common ≥ 1/10
Common ≥1/100 and <1/10
Uncommon ≥ 1/1,000 and <1/100
Rare ≥ 1/10,000 and <1/1,000
Very rare < 1/10,000

10. Avandia (Rosiglitazone) Adverse Reactions - SPC

11. 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

12. 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

13. 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

14. 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

15. 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)

16. 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

17. 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
+1 0 0
antagonist was administered?
Did the AR reappear when drug was readministered? +2 -1 0
Are there alternate causes [other than the drug] that could solely have
-1 +2 0
caused the reaction?
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
+1 0 0
know n to be toxic?
Was the reaction more severe when the dose was increased, or less
+1 0 0
severe when the dose was decreased?
Did the patient have a similar reaction to the same or similar drugs in any
+1 0 0
previous exposure?
Was the adverse event confirmed by objective evidence? +1 0 0

18. 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

19. 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)

20. 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

21. 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

22. 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

23. 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

24. System of Safety Data Gathering
Clinical Trials
Healthcare
Professionals
Pre-Approval
Post-Approval
National Regulatory
Patients
Authority
Pharmaceutical
Companies
International Safety
Databases

25. 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)

26. 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 patient-
years).

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

27. Cerivastatin Case Study

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

28. 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

29. 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

30. 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

31. Pre-clinical Studies
Standard toxicology pre-clinical tests are:

Acute toxicity

Repeat use toxicity

Local irritation tests

Pyrogenity

Reproductive toxicity

Mutagenity

Carcinogenity

32. 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

33. 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

34. Rationale for Post-Marketing Surveillance

Tests in animals are insufficient to predict 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

35. 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

36. 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

37. 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

38. How to Report - Slovakia
SPRÁVA O NEŽIADUCOM ÚČINKU LIEKU
Iniciálky pacienta:: Dátum nar.: Sex: muž - žena
Dát um nežiaducej reakcie:..................................................
Nežiaduce reakcie:

Guidance No. 15/2004 on reporting 1................................…................................... 4..................................................................
of side effects of registered 2......................................................................
3......................................................................
5..................................................................
6..................................................................
medicines Vznikla reakcia u
hospitalizovaného áno - nie
pacienta?
hospitalizácia pre
Form downloadable from SIDC site
o predĺženie hospitalizácie?
 NÚL?
bol ohrozený život
o trvalé poškodenie pacienta?
http://www.sukl.sk
pacienta?
umrel pacient? Dátum úmrtia: Príčina smrti:
Podozrivý liek: Podanie Dávka od - do Diagnóza
Heathcare professional are
1

Ostatné
obligated to report suspected
lieky
2
adverse drug reactions with 3
4
presumed casual relationship 5
6
7

In 2004 there were about 900 8
reports mostly from physicians.
9
Prestal sa liek podávať? áno-nie
Number of reports is significantly Upravila sa reakcia po vynechaní lieku ?
Objavila sa reakcia po novom podaní ?
áno- nie- neviem
áno- nie- neviem- nepodal sa
lower compared to other EU Používal pacient liek v minulosti? áno - nie - neviem
countries
Anamnéza: o NÚL na lieky? Aké ?
o alergia? o fajčenie? o tehotenstvo? o alkohol, drogy
Je správa z klinickej skúšky? áno - nie z epidemiol. štúdie? áno - nie
Odbornosť lekára: nemocničný lekár? áno - nie
Meno lekára: Adresa zariadenia:

39. 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

40. 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.

41. 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

42. 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

43. Regulatory Actions

Safety warnings

Labeling change/changes in SPC

Withdrawal

44. 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

45. 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

46. 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

47. 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

48. 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

49. 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

50. 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

51. Where to find information

Monographies/Compendia
− Davies: Textbook of adverse effects
− Dukes: Meyler`s side effects of drugs

Journals
− Regulatory Toxicology and Pharmacology

Newsletters
− Drug Safety Update – published by MHRA

Regulatory Agencies
− FDA: http://www.fda.gov/
− EMEA: http://www.emea.europa.eu/
− SIDC: http://www.sukl.sk

52. Thank You For Your Attention !