Drug Safety and Post-Marketing Surveillance

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

Post-marketing surveillance = Phamacovigilance

New drug (in the context of pharmacovigilance) Any drug product that has not been marketed for more than five years

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

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.Essential elements in this definition are the pharmacological nature of the effect, that the phenomenon is unintended, and that there is no overt overdose.

Adverse drug reaction

A response to a drug which is noxious and unintended, and which occurs at doses normally used in man.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).

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.

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

Serious Adverse Event:  a. life-threatening or fatal b. 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

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. 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

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 case

9600 patients                           for 2 cases

13 000 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-Marketing
Number of Patients	100-1000	>1000
Type of Patients	Precise diagnosis, selected patients	No patient  selection, associated  diseases, no age limits
Other concomitant treatments	Usually  excluded	Possible
Duration	Well  defined	Undefined
Follow-up	Careful ,detailed, constant	Casual, patient loss 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.    

What to report?

·         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.

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)

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

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)

Rationale for Pharmacovigilance

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

Why incidence of ADRs is not diminishing

·         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

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

PPosted by:-Indian Biological Sciences and Research Institute, NOIDA