drug safety and post-marketing surveillance

1 JICWELS Course, 27 July 2001 WHO - EDM

Drug safety and Post-marketing

surveillance

Dr Valerio Reggi, HTP/EDM/QSM27 July 2001


Outline of presentation

• Definitions• Rationale for

pharmacovigilance• WHO’s monitoring

programme• Options for countries with

limited resources


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


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


New drug (in the context of pharmacovigilance)

Any drug product that has not been marketed for more than five years

Definitions


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


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


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


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


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


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


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


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


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



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 .


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



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.


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.



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



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



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.



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)



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)



Every single problem related to the use of a drug, because probably nobody else is collecting such information!

What to report? (3)


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


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


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)


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



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?



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



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


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


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



Official member countriesAssociate member countries

WHO Drug Monitoring ProgrammeParticipating countries 1999

58 countries have joined the programme


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


WorkCollection and processing of dataData utilization Information exchange and feedbackEducation, training and advice HarmonizationResearchEvaluation

Function Signal generation - identification of previously unknown adverse drug reactions



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


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



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


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?


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



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



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

drug safety and post-marketing surveillance

Health & Medicine