drug safety and post-marketing surveillance
TRANSCRIPT
1 JICWELS Course, 27 July 2001 WHO - EDM
Drug safety and Post-marketing
surveillance
Dr Valerio Reggi, HTP/EDM/QSM27 July 2001
2 JICWELS Course, 27 July 2001 WHO - EDM
Outline of presentation
• Definitions• Rationale for
pharmacovigilance• WHO’s monitoring
programme• Options for countries with
limited resources
3 JICWELS Course, 27 July 2001 WHO - EDM
Rationale for Rationale for pharmacovigilancepharmacovigilanceRationale for Rationale for pharmacovigilancepharmacovigilance
Drug safety and Post-marketing surveillance
DefinitionsDefinitionsDefinitionsDefinitions
WHO’s monitoring WHO’s monitoring programmeprogrammeWHO’s monitoring WHO’s monitoring programmeprogramme
Opions for countries Opions for countries with limited resourceswith limited resourcesOpions for countries Opions for countries with limited resourceswith limited resources
4 JICWELS Course, 27 July 2001 WHO - EDM
Phamacovigilance
Set of methods that aim at identifying and quantitatively assess the risks related to the use of drugs in the entire population, or in specific population subgroups
Definitions
Post-marketing surveillance = Phamacovigilance
5 JICWELS Course, 27 July 2001 WHO - EDM
New drug (in the context of pharmacovigilance)
Any drug product that has not been marketed for more than five years
Definitions
6 JICWELS Course, 27 July 2001 WHO - EDM
PSUR (Periodic Safety Update Report)
A report containing information collected by marketing authorisation holders through pharmacovigilance activities. It is usually required by regulatory authorities for drugs that have not been marketed for more than five years
Definitions
7 JICWELS Course, 27 July 2001 WHO - EDM
Essential elements in this definition are the pharmacological nature of the effect, that the phenomenon is unintended, and that there is no overt overdose.
Side effect
Any unintended effect of a pharmaceutical product occurring at doses normally used in man, which is related to the pharmacological proprieties of the drug.
Definitions
8 JICWELS Course, 27 July 2001 WHO - EDM
Important: it concerns the response of a patient, in which individual factors may play an important role, and the phenomenon is noxious (an unexpected therapeutic response, for example, may be a side effect but not an adverse reaction).
Adverse drug reaction
A response to a drug which is noxious and unintended, and which occurs at doses normally used in man.
Definitions
9 JICWELS Course, 27 July 2001 WHO - EDM
Unexpected adverse drug reaction
An adverse reaction, the nature or severity of which is not consistent with market authorisation, or expected from the characteristics of the drug. Predominant element is that the phenomenon is unknown.
Definitions
10 JICWELS Course, 27 July 2001 WHO - EDM
Adverse event/adverse experience
Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment
Definitions
11 JICWELS Course, 27 July 2001 WHO - EDM
Serious adverse event:
a. life-threatening or fatalb. cause or prolong hospital admissionc. cause persistent incapacity or disability; ord. concern misuse or dependence
ICH E6 guideline: substantially same as above plus: - congenital anomaly/birth defect
Definitions
12 JICWELS Course, 27 July 2001 WHO - EDM
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
Definitions
13 JICWELS Course, 27 July 2001 WHO - EDM
Causality assessment
Case reports describe suspected adverse drug reactions.
To determine likelihood of a causal relationship between drug exposure and adverse events:- 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.
Definitions
14 JICWELS Course, 27 July 2001 WHO - EDM
Different types of adverse events
Type A effects (‘drug actions’):
• due to pharmacological effects,• fairly common, • dose related (i.e. more frequent or severe with high
doses) and may often be avoided by using doses which are appropriate to the individual patient,
• can usually be reproduced and studied experimentally and are often already identified before marketing.
Drug interactions - may be classified as Type A effects, although they are restricted to a defined sub-population of patients, i.e. those taking interacting drugs
15 JICWELS Course, 27 July 2001 WHO - EDM
Different types of adverse events
Type B effects (‘patient reactions’):
occur in only a minority of predisposed, intolerant patients, little or no dose relationship, generally rare and unpredictable, sometimes serious, difficult to study .
16 JICWELS Course, 27 July 2001 WHO - EDM
Examples of Type B effects (‘patient reactions’):
Drug intolerance:
toxic reactions, not related to overdose or diminished elimination
Drug idiosyncrasy:genetically determined abnormal reaction to the drug that may be related to metabolic or enzyme deficiency
Drug allergy:immunologically meditated reaction that is characterised by specificity, involvement of antibodies or lymphocytes and re-occurence in case of new contact with the drug
Pseudoallergic reactions:the same clinical symptoms as allergic reaction but without immunological specificity
17 JICWELS Course, 27 July 2001 WHO - EDM
Different types of adverse events
Type C effects:
• the use of a drug increases the frequency of a ‘spontaneous’ disease,
• may be both serious and common (and include malignant tumours) and may have pronounced effects on public health,
• often relate to long term effects,• there is often no suggestive time relationship and the
connection may be very difficult to prove.
18 JICWELS Course, 27 July 2001 WHO - EDM
DefinitionsDefinitionsDefinitionsDefinitions
Drug safety and Post-marketing surveillance
WHO’s monitoring WHO’s monitoring programmeprogrammeWHO’s monitoring WHO’s monitoring programmeprogramme
Opions for countries Opions for countries with limited resourceswith limited resourcesOpions for countries Opions for countries with limited resourceswith limited resources
Rationale for Rationale for pharmacovigilancepharmacovigilanceRationale for Rationale for pharmacovigilancepharmacovigilance
19 JICWELS Course, 27 July 2001 WHO - EDM
Rationale for pharmacovigilance
Information obtained prior to first marketing is inadequate to cover all aspects of drug safety: tests in animals are insufficiently 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 women) or drug interactions is often not available.
20 JICWELS Course, 27 July 2001 WHO - EDM
Rationale for pharmacovigilance
To be sure to detect an ADR that occurs once per 2000 patients treated, we need to treat:
6000 patients for 1 case9600 patients for 2 cases13 000 patients for 3 cases
The number of patients involved in pre-marketing studies has been increasing but is still inadequate to provide information on less frequent ADR
21 JICWELS Course, 27 July 2001 WHO - EDM
Rationale for pharmacovigilance
Efficacy Post-marketingNumber ofpatients
100-1000 >10000
Type ofpatient
Precisediagnosis,selectedpatients
No patientselection,associateddiseases, no agelimits
Otherconcomitanttreatments
Usuallyexcluded
Possible
Duration Welldefined
Undefined
Follow-up Careful,detailed,constant
Casual, patientless informed
22 JICWELS Course, 27 July 2001 WHO - EDM
Rationale for pharmacovigilance
Pharmacovigilance is needed in every country, because there are differences between countries in the occurrence of adverse drug reactions because of differences in: drug production distribution and use (e.g. indications, dose, availability) genetics, diet, traditions of the people pharmaceutical quality and composition (excipients) of locally produced pharmaceutical products the use of non-orthodox drugs (e.g. herbal remedies) which may pose special toxicological problems, when used alone or in combination with other drugs.
23 JICWELS Course, 27 July 2001 WHO - EDM
Rationale for pharmacovigilance
All suspected adverse reactions - known or not, serious or not - because:
necessary to create notification culture where instinctive response to any suspected adverse drug reaction is to report it
healthcare professionals need to learn how to notify,
pharmacovigilance centres need experience in assessment, coding and interpretation.
What to report? (1)
24 JICWELS Course, 27 July 2001 WHO - EDM
Rationale for pharmacovigilance
ADR associated with radiologic 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 (e.g. antibiotics) overdose (because may cast doubt on safety of a
drug)
What to report? (2)
25 JICWELS Course, 27 July 2001 WHO - EDM
Rationale for pharmacovigilance
Every single problem related to the use of a drug, because probably nobody else is collecting such information!
What to report? (3)
26 JICWELS Course, 27 July 2001 WHO - EDM
Some dates in the history of pharmacovigilance
1848
The Lancet starts collecting notifications of side effects after a death caused by anaesthesia
1906
US Federal Food and Drug Act requires that pharmaceuticals be “pure” and “free of any contamination”
1937
USA: 107 lethal cases after diethylenglycol was mistakenly used to solubilize sulphanilamides
1952
France: 100 lethal cases after diethyl tin diodide was mistakenly used in a skin preparation
27 JICWELS Course, 27 July 2001 WHO - EDM
1959-61
Reports of foetal abnormalities in relation with the use of a new sleep-inducing drug thalidomide (biggest number in Germany)
1962
USA revised law requiring to prove safety and efficacy before issuing marketing authorisation
1964
UK starts “yellow cards” system 1967
WHO’s International Drug Monitoring Programme 1976
Drugging of the Americas: inadequacy of safety information
Some dates in the history of pharmacovigilance
28 JICWELS Course, 27 July 2001 WHO - EDM
Lessons learnt from the thalidomide catastrophy
Not all drugs good in animals are good for humans (thalidomide was very safe in pregnant rats …)
Even very dangerous drugs can be valuable if safety measures could be followed (thalidomide is effective in treatment of leprosy type II reactions, erythema nodosum leprosum)
Safety measures cannot be followed 100% (in some countries where thalidomide has been used for leprosy new thalidomide children have been reported)
29 JICWELS Course, 27 July 2001 WHO - EDM
Pomeranz et al., JAMA, 1998;279:1200-1205
In the USA: ADRs are among the top 10 causes of death Annually 2 216 000 ADRs in inpatients and 106 000
deaths possibly related to use of pharmaceuticals In 1994, 4.6% of all deaths may be due to
pharmaceuticals Comparison: accidents 90 523 deaths, lung diseases
101 077 deaths, stroke 150 108 deaths
Rationale for pharmacovigilance
30 JICWELS Course, 27 July 2001 WHO - EDM
the number of different drugs used by a single patient is increasing
elderly population is increasing and elderly are more sensitive to ADR, use more drugs and more drugs concomitantly
more sophisticated and widespread pharmacovigilance improves availability of information
Why incidence of ADRs is not diminishing?
Rationale for pharmacovigilance
31 JICWELS Course, 27 July 2001 WHO - EDM
Old survey: 1001 patients older than 45 (USA, 1982)
47% of medical doctors never asked any questions about OTC drugs
45% of medical doctors never asked which other drug(s) a patient is already taking
63% of pharmacists never gave any information about ADRs
59% of medical doctors never explained what to do if an ADR occurs
59% of patients never make any notes on what drugs they take and when
Rationale for pharmacovigilance
32 JICWELS Course, 27 July 2001 WHO - EDM
Herbal and traditional medicines also have safety problems
Echinacea purpurea - Australian Adverse Drug Reaction Bulletin, v.18, No.1, 1999: Popular in many countries for prophylaxis and
treatment of common cold In Australia 37 reports of ADRs associated with
Echinacea in 2 years:
• 21 allergic reactions, 9 bronchospasm, 8 dyspnoea, 5 urticaria, 4 angina
• 12 patients had previous history of asthma, allergic rhinitis, conjunctivitis, hay fever
Conclusion: Echinacea may be dangerous in those patients who have history of allergic diseases
33 JICWELS Course, 27 July 2001 WHO - EDM
Are natural medicines safer? Many drugs come from nature e.g. Vinca alkaloids
So-called “natural” or traditional medicines in many cases have no documented evidence of both efficacy and safety.
All types of products should be included in national pharmacovigilance activities
34 JICWELS Course, 27 July 2001 WHO - EDM
Examples of products removed from the EU markets in 1998
Mibefradile (Posicor) - calcium channel blocker, cardiac toxicity
Tolcapone (Tasmar) - antiparkinson, hepatotoxic
Sertindole (Serdolect) - atypical neuroleptic, arrhythmias
All were registered in the EU by centralised procedure and withdrawn within 2 years due to unfavourable benefit/risk ratio
Rationale for pharmacovigilance
35 JICWELS Course, 27 July 2001 WHO - EDM
DefinitionsDefinitionsDefinitionsDefinitions
Rationale for Rationale for pharmacovigilancepharmacovigilanceRationale for Rationale for pharmacovigilancepharmacovigilance
Drug safety and Post-marketing surveillance
Opions for countries Opions for countries with limited resourceswith limited resourcesOpions for countries Opions for countries with limited resourceswith limited resources
WHO’s monitoring WHO’s monitoring programmeprogrammeWHO’s monitoring WHO’s monitoring programmeprogramme
36 JICWELS Course, 27 July 2001 WHO - EDM
Official member countriesAssociate member countries
WHO Drug Monitoring ProgrammeParticipating countries 1999
58 countries have joined the programme
37 JICWELS Course, 27 July 2001 WHO - EDM
WHO Collaborating Centre in Uppsala(Uppsala Monitoring Centre - UMC)
Established in 1978 as Swedish Foundation Based on agreement between WHO and Swedish
Government Originally financial contributions from Sweden
(practically ceased by today) Swedish administrative board (will have international
board in future) WHO headquarters responsible for policy Operational arm of WHO Drug Monitoring Programme
38 JICWELS Course, 27 July 2001 WHO - EDM
WorkCollection and processing of dataData utilization Information exchange and feedbackEducation, training and advice HarmonizationResearchEvaluation
Function Signal generation - identification of previously unknown adverse drug reactions
WHO Collaborating Centre in Uppsala(Uppsala Monitoring Centre - UMC)
39 JICWELS Course, 27 July 2001 WHO - EDM
Principal sources of information on drug safety
Pre-clinical studies Clinical studies (pre- and post-marketing) Spontaneous adverse reaction reporting
national international
Epidemiological studies case-control (one effect/many risk factors) cohort (one risk factor/many possible effects)
Data collected for other purposes routine statistics databases of prescription and outcomes
40 JICWELS Course, 27 July 2001 WHO - EDM
Problems
Many countries have started ADR (voluntary) reporting schemes but:
Not all reports meet requirements of WHO Uppsala Monitoring Centre
Large numbers of poor quality reports
Underreporting is still a big problem, even in the most developed countries
WHO Collaborating Centre in Uppsala(Uppsala Monitoring Centre - UMC)
41 JICWELS Course, 27 July 2001 WHO - EDM
What DRA should do after identifying safety problems?
Indications/use Dosing instructions Contra-indications Interactions Pregnancy/lactation Warnings/precautions Undesirable effects Over dosage
Edit product information:
Benefit/risk evaluation
Withdraw marketing authorisation
42 JICWELS Course, 27 July 2001 WHO - EDM
DefinitionsDefinitionsDefinitionsDefinitions
Rationale for Rationale for pharmacovigilancepharmacovigilanceRationale for Rationale for pharmacovigilancepharmacovigilance
Drug safety and Post-marketing surveillance
WHO’s monitoring WHO’s monitoring programmeprogrammeWHO’s monitoring WHO’s monitoring programmeprogramme
Opions for countries Opions for countries with limited resourceswith limited resourcesOpions for countries Opions for countries with limited resourceswith limited resources
43 JICWELS Course, 27 July 2001 WHO - EDM
Be cautious in authorising new drugs Not all new drugs represent tremendous therapeutic advances Not all therapeutic advances can fully benefit all situations
Establish appropriate regulatory requirements to keep your national authority up to date Obtain evidence of actual marketing in countries with
established ADR monitoring practices Obtain copy of regular reports submitted to advanced DRAs
What are the options when resources are limited?
44 JICWELS Course, 27 July 2001 WHO - EDM
Establish collaboration with national institutions, associations, and NGOs often information is available in books, magazines, Internet national institutions may have these materials available professional associations and NGOs may have resources to
provide useful input starting a centre in a separate institution (e.g. university hospital)
will not draw from DRA resources and will contribute to building a risk/benefit culture in the use of drugs
What are the options when resources are limited?
45 JICWELS Course, 27 July 2001 WHO - EDM
Establish collaboration with other DRAs and with Uppsala Monitoring Centre most advanced DRAs may share evaluation reports
and risk/benefit evaluations most advanced DRAs have useful information on their
web sites UMC is able to provide information, advice and
assistance www.who-umc.org
What are the options when resources are limited?
46 JICWELS Course, 27 July 2001 WHO - EDM
Benefit/risk assessment - a crucial concept at thevery basis of many regulatory decisions
Benefit/risk assessment - a crucial concept at thevery basis of many regulatory decisions
Public health need - PMS is vital to achieve safeand rational use of medicines
Public health need - PMS is vital to achieve safeand rational use of medicines
Decisions appropriate to needs and resources- emphasis on “adapting” rather than “copying”
Decisions appropriate to needs and resources- emphasis on “adapting” rather than “copying”
Conclusion
Drug safety and post-marketing surveillance