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Pharmacovigilance
Vladimir Patras, PharmD, MBAVladimir Patras, PharmD, MBA
Clinical Pharmacology Seminar
Department of Pharmacology and Toxicology, Faculty of Pharmacy
Withdrawn Drugs (in the US, since 2000)Drug Year ReasonLumiracoxib 2008 HepatotoxicityAprotinin 2008 Kidney and cardiovascular toxicityTegaserod 2007 Cardiovascular ischemic eventsXimelagatran 2006 HepatotoxicityValdecoxib 2005 Dermatology adverse eventsPemoline 2005 HepatotoxicityRofecoxib 2004 Thrombotic cardiovascular eventsLevomethadyl 2003 Fatal ArrhytmiaRapacuronium 2001 Risk of fatal bronchospasmCerivastatin 2001 RhabdomyolosisTrovafloxacin 2001 HepatotoxicityAmineptine 2000 Hepatotoxicity, dermatological side effects, abuse potentialCisapride 2000 Cardiac arrhythmiasTroglitazone 2000 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Some drugs were withdrawned and reintroduced after further studies or special safety measures – Natalizumab withdrawn in 2005 and reintroduced in 2006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 life-threatening, 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 FrequencyVery commonCommonUncommonRareVery rare < 1/10,000
≥ 1/10 ≥1/100 and <1/10≥ 1/1,000 and <1/100≥ 1/10,000 and <1/1,000
Avandia (Rosiglitazone) Adverse Reactions - SPC
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)
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 specif icantagonist 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 havecaused 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 f luids] in a concentrationknow n to be toxic? +1 0 0
Was the reaction more severe when the dose was increased, or lesssevere when the dose was decreased? +1 0 0
Did the patient have a similar reaction to the same or similar drugs in anyprevious 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
PharmaceuticalCompanies
Patients National RegulatoryAuthority
International SafetyDatabases
HealthcareProfessionals
Clinical Trials
Pre-Approval
Post-Approval
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 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
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
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
Guidance No. 15/2004 on reporting of side effects of registered medicines
Form downloadable from SIDC site http://www.sukl.sk
Heathcare professional are obligated to report suspected adverse drug reactions with presumed casual relationship
In 2004 there were about 900 reports mostly from physicians. Number of reports is significantly lower compared to other EU countries
SPRÁVA O NEŽIADUCOM ÚČINKU LIEKUIniciálky pacienta:: Dátum nar.: Sex: muž - žena
Dátum nežiaducej reakcie:..................................................Nežiaduce reakcie:
1................................…................................... �
2...................................................................... �
3...................................................................... �
4.................................................................. �
5.................................................................. �
6.................................................................. �
Vznikla reakcia uhospitalizovanéhopacienta?
áno - nie
hospitalizácia preNÚL?
o predĺženie hospitalizácie?
bol ohrozený životpacienta?
o trvalé poškodenie pacienta?
umrel pacient? Dátum úmrtia: Príčina smrti:
Podozrivý liek: Podanie Dávka od - do Diagnóza
1
Ostatnélieky
2
3
4
5
6
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? 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:
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
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
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