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Of late, every few months we hear of a product being withdrawn due to unexpected adverse events, often life threatening. In such a situation, pharmacovigilance should be regarded as a public health function that monitors the safety of medicines while taking action to reduce their risks and increase benefits .

Pharmacovigilance is the study of adverse reactions to marketed drugs, their assessment, understanding and actions to minimize risk to patients

Need for pharmacovigilance

  • During the premarketing stage however close one tries to mimic the human pharmacokinetics in animals it is not a foolproof method. Pharmacokinetics can vary with species, so even in dogs, rats, mice or monkeys which are considered close to humans, one may not be able to obtain the same exposure without causing toxicities. Hence often animal models may be deficient and insufficiently predictive of human safety .

  • The information collected during the pre-marketing phase of a drug is inevitably incomplete with regard to possible adverse reactions simply by virtue of the limited number of patients it has been tried on. e.g if the total sample size from all premarketing studies is 10,000, we will be able to identify only those adverse effects whose incidence is 1:10,000. If a gender bias existed it would be still less

  • Further, in clinical trials, due to a list of exclusion criteria , selected patients are included and the conditions and duration of use differ from those in clinical practice

  • 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 incomplete or not available.

  • Pharmacovigilance helps us keep track of all adverse events of a drug as it is used by the larger population, and preventive actions for population safety can be taken in a timely manner


International actions towards ideal pharmacovigilance

The Thalidomide disaster in early 60s drew public attention to long term adverse effects of drugs and the need for constant monitoring. Gradually every country had its own set of rules regarding safety monitoring and regulatory actions there from. But it was also required to coordinate this effort between countries.

Various world bodies help coordinate these activities between countries, companies, investigators, health care providers, patients, regulatory bodies and other stakeholders. They provide guidelines so as to have a common platform for sharing information amongst stakeholders. Each regulatory authority like the FDA, EMEA or DCG(I) have their own guidelines. Some international bodies are

  • WHO – Since 1978, the WHO international drug monitoring programme has been carried out at Uppsala monitoring centre in Sweden. This center provides data, references, consultation and training resources to various regulatory bodies, health professionals, researchers and also the pharmaceutical industry all over the world. The centre also maintains WHOART, a dictionary meant to serve as a basis for rational coding of adverse reaction terms

  • CIOMS – Council for International Organizations of Medical Sciences is an international, nongovernmental, not-for-profit organization established jointly by WHO and UNESCO in 1949.Apart from guidelines on Ethics and conduct of clinical research, it also publishes guidelines on ADR reporting. In fact the CIOMS form is the template commonly used as such or with minor modifications for ADR reporting around the world. It forms an important link between the industry & regulatory authorities for the purpose of exchange of ADR information

  • ICH – International Conference on Harmonization also provides guidelines on ADR reporting in E2D.

With so much international focus on drug safety one comes across a long list of drugs that have been withdrawn over the past several years. Some examples are

Drug Year of launch Year of Withdrawal Reason
Phenylbutazone 1940s 1970s Bone marrow suppression
Thalidomide 1956 1962 Phocomelia
Terodiline HCl 1965 1991 Torsade de pointes
Practolol 1970 1975 Blindness
Nomifensine 1976 1986 Haemolytic anaemia
Benoxaprofen 1982 1982 Renal & liver failure, Bone marrow depression
Terfenadine 1985 1997 Torsade de pointes
Temafloxacin 1992 1992 Haemolytic anaemia
Cisapride 1993 2000 Torsade de pointes
Cerivastatin 1997 2001 Rhabdomyolysis, death
Bromfenac 1997 1998 Hepatotoxicity

From the table it appears that international efforts are bearing fruit and we are detecting fatal flaws early. But is this really true?

For every Benoxaprofen or Temafloxacin we have a Terfenadine or a Cisapride. The reason for this dichotomy lies in the aetiology of adverse reactions.

Adverse reactions could be classified Type A or type B. The type A reactions are accentuations of the pharmacological effects and hence expected while the Type B reactions are the ones that are not very common, idiosyncratic in nature and may not have a dose response relationship. These are often identified a long time after the launch of the drug

Another way of classifying adverse reactions is the A to F classification

  • Type A – Augmented - excess desired effect as in case of Anti diabetics, known side effect like asthma with , beta blockers
  • Type B – Bizarre anaphylaxis - idiosyncratic
  • Type C – Chronic - long term exposure
  • Type D – Delayed – carcinogenesis breast Ca in relation to OCs
  • Type E – Post termination of therapy - antidepressants
  • Type F – Failure of effect – contraceptives, vaccines

It is obvious that Types B,C,D and to some extent E are the ones that may take years to be identified in numbers sufficient for the regulators to take strong action. Efforts have created an awareness and we are ever vigilant about ADRs, but the identification has to take its own course in time.

Regulations for safety reporting

Regulators across the world have laid down specific and stringent guidelines for reporting. They specify the nature of events to be reported, the contents of the report and the timelines that have to be adhered to. Submissions can be submission of death cases, Serious Adverse Events (SAEs), Suspected Unexpected Serious Adverse Events (SUSARs) and in the form of spontaneous reports, annual reports, Periodic Safety Update Reports(PSURs) etc.

Regulators could undertake surprise audits of the pharmacovigilance departments of pharma companies. Generally the following events act as a trigger for such inspections

  • Non-submission of data
  • Submission of data after the deadline agreed in the letter of undertaking from the company, without previous agreement from the Competent Authority
  • Failure to implement a specific obligation
  • Failure to implement a follow-up measure
  • Poor quality of a report requested as a follow-up measure
  • Poor quality of a report requested as a specific obligation
  • Failure to implement an urgent provisional measure
  • Info from another authority of the above above.


Regulatory action

If any irregularity is observed during the audit or inspection, the regulatory action is decided on a case to case basis but generally considering public impact of the action. It could be one or more of the list below

  • Awareness Education & assistance to comply
  • Inspection
  • ‘Name & shame’, 483s in US
  • Warning
  • Urgent safety restriction
  • Variation, Suspension or Revocation of the Marketing Authorisation
  • Prosecution



  • http://ec.europa.eu/health/human-use/pharmacovigilance/index_en.htm
  • Reporting ADRs, CIOMS publication 1999
  • Post-approval safety data management: definitions and standards for expedited reporting .E2d . ICH publication 2003
  • Karen Hedenmalm. Hazards of Drug Therapy. Upsala Dissertations 2005;downloaded 2012jan
  • Council for International Organizations of Medical Sciences,(CIOMS VI, 2005)
Dr. Vishwas Sovani November 2012

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Pharmacovigilance, drug safety, adverse reaction, need of pharmacovigilance, product withdrawal