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Unit-9 Pharmacovigilence

By Abdullah Khan

Introduction Definitions: Drug, PV, AE Drug Development Adverse Event Need for PV-Clinical Trails and Post Marketing PV in countries Reporting Benefits- Public and drug manufacturer Rationale Recall

World health organization (WHO, 2004) defines pharmacovigilance as the science and activities relating to the detection, assessment, understanding, and prevention of adverse drug reactions (ADRs), or any other medicine-related problems.

Safety monitoring and evaluation throughout whole life-cycle of a product

Encompasses non-clinical, clinical, post-marketing safety data

Early 20th century there were no controls over the drug development process. Claims over treating diseases and uncontrolled marketing. Safety or effectiveness of the drug- NOT a concern for government.

1883 Dr. Harvey Wiley initiated the campaign for Federal law for Food and Drugs Act that was finally passed in 1906. The law was further tightened following incidents such as poisoning of children by Sulphanilamide and the Thalidomide tragedy. 1938 Federal Food, Drug, and Cosmetic Act.

Substance or mixture of substances used for diagnosis, treatment, mitigation or prevention of disease or disorders. Used for restoring correcting or modifying organic functions in human beings or animals.

Animal experiments
Clinical trials Epidemiological methods

Observational studies case reports case series

Post-Marketing Surveillance (PMS) Prescription event monitoring Cohort studies intensive hospital monitoring Case-control studies Record-linkage Meta-analysis

Preclinical Testing IVESTIGATIONAL NEW DRUG(IND) Application Clinical Testing Phase I Clinical Testing Phase II Clinical Testing Phase III New Drug Application Clinical TestingPhase IV
IB,ICF, AE, Placebo, Blinding, randomized, Serious, Concomitant medication, Causality,

They are usually small trials, recruiting only a few patients. E.g. The trial may be open to people with any type of cancer When laboratory testing shows that a new treatment might help treat the cancer, phase 1 trials are done to find out The safe dose range What the side effects are How the body copes with the drug If the treatment shrinks the cancer?

Not all treatments tested in a phase 1 trial make it to a phase 2 trial. These trials may be for people who all have the same type of cancer, or who have several different types of cancer. Phase 2 trials aim to find out If the new treatment works well enough to test in a larger phase 3 trial Which types of cancer the treatment works for More about side effects and how to manage them More about the best dose to use Phase 2 trials are often larger than phase 1.


These trials compare new treatments with the best currently available treatment (the standard treatment). Phase 3 is sometimes written as phase III. These trials may compare A completely new treatment with the standard treatment Different doses or ways of giving a standard treatment A new way of giving radiotherapy with the standard way Phase 3 trials usually involve many more patients than phase 1 or 2


Phase 4 trials are done after a drug has been shown to work and has been granted a license. The main reasons for running phase 4 trials are to find out More about the side effects and safety of the drug What the long term risks and benefits are How well the drug works when its used more widely


A branch of medical science that deals with the incidence, distribution, and control of disease in a population The sum of the factors controlling the presence or absence of a disease or pathogen Epidemiology studies involves

Observational studies case reports case series




Informed Consent Form- subject voluntarily confirms to participate, made aware of all aspects Placebo- A substance containing no medication, given to reinforce a patient's expectation to get well (an inactive substance or preparation used as a control to determine the effectiveness of a medicinal drug) GUIDELINES (WMA declaration of Helsinki) Blinding/Masking- one or more parties kept unaware of the treatment assignment -Single blinding subjects unaware -double blinding subjects, investigators, monitor, data analysts are also unaware Randomized- subjects assigned randomly to treatment or control ( chance to reduce bias) Serious- death, lethal threat, hospitalization, disability, birth defect Concomitant medication- medications used by patients in a clinical trial, other than the investigational drug. ( includes those drugs used to treat AE of investigational drug) Causality- that AE was due to the medicine in question

Any unfavorable and unintended sign, symptom or a disease temporarily associated with the use of medicinal product (drug), whether or not considered related to the medicinal product. can be lab finding too or symptom or disease temporally associated with use of IP, whether or not related to the IP


There is a need to monitor the effects of drugs during the clinical trials and after its launch in a market.

Because adverse events can even happen during the clinical trials and event after its launch market.


too few patients too simple

- normally < than 1500

- use patients without complications, other medical conditions

too narrow
too brief

- limited indications
- limited time

too median

- very old/very young patients, pregnant women not included

After the completing preclinical studies in animals, first time trial drug will be administered to the human. At this time the drug will act in different way to the human body. Chances of adverse will also persist.

At the time of approval, clinical trial data are available on limited numbers of patients treated for relatively short periods

Once a product is marketed, large numbers of patients may be exposed, including:

Patients with co-morbid illnesses Patients using concomitant medications Patients with chronic exposure Genetic diversity in large population


The evaluation of risk must be conducted in the context of the patient benefit derived from treatment, the severity of the condition being treated, and other objective and subjective factors (such as the patients values).


After marketing, new safety information may become available:

Through use of the product domestically or in other countries Through use of other drugs in the same class From preclinical studies From pharmacologic studies From clinical trials


There are differences among countries ( and even within countries ) in the occurrence of ADRs (Adverse drug reactions) and other drug related problems

Differences in diseases Prescribing practices Genetics Diet Traditions/lifestyle of people Drug manufacturing processes Drug distribution The use of drugs ( dose, indications and availability)





Health authority


Consumer Physician Healthcare prof Sponsor Health Authority


The following pharmacovigilance processes should be considered as critical include: Continuous safety profile monitoring and benefit risk evaluation of authorized medicinal products; Establishing, assessing and implementing risk management systems and evaluating the effectiveness of risk minimization Collection, processing, management, quality control, follow up for missing information, coding, classification, duplicate detection, evaluation and timely electronic transmission of individual case safety reports (ICSRs) from any source; Signal management Scheduling, preparation (including data evaluation and quality control), submission and assessment of periodic safety update reports;


Meeting commitments and responding to requests from competent authorities , including provision of correct and complete information; Interaction between the pharmacovigilance and product quality defect systems; Communication about safety concerns between marketing authorisation holders and competent authorities, in particular notifying changes to the risk-benefit balance of medicinal products; Communicating information to patients and healthcare professionals about changes to the risk-benefit balance of products for the aim of safe and effective use of medicinal products; Keeping product information up-to -date with the current scientific knowledge, including the conclusions of the assessment and recommendations from the applicable competent authority; Implementation of variations to marketing authorizations for safety reasons according to the urgency required



New drugs Report all suspected reactions including minor ones For established or well known drugs All serious, unexpected, unusual ADRs Change in frequency of a given reaction ADRs to generics not seen with innovator products ADRs to traditional medicines

All suspected drug-drug, drug-food, drug-food supplement interactions

Statement highlighting marine source of supplements such as glucosamine so that can be avoided by those with allergy to sea food

ADRs associated with drug withdrawals ADRs due to medication errors

Eg. vincristine given IT

ADRs due to lack of efficacy or suspected pharmaceutical defects

ADR associated vaccines, diagnostics, drugs used in traditional medicine, herbal remedies, cosmetics, medical devices and equipment lack of efficacy and suspected pharmaceutical defects overdose (because may cast doubt on safety of a drug)


NOTE: When in doubt- Always report!!



Spontaneous reporting of suspected adverse drug effects is central to pharmacovigilance which is the systematic search for signals of drug toxicity. When such a signal is detected it has to be verified, explored, and understoodrealizing that the drug may be acceptably safe if used by individuals who are not at especially high risk by virtue of genetic constitution, metabolism, or other characteristics that could alter individual risk.


Government Pharmaceutical Industry Hospitals and academia Medical and pharmaceutical associations medicines information centers Health professionals Patients Consumers The media?? World Health Organization

Each of the stakeholdersthe patient, physician, pharmaceutical company, academic investigator, governmentmay have a different perspective on the same set of evidence.

For example, A patient may be willing to accept a high risk of side-effects for benefits of the treatment for a condition that might be considered trivial by others. A regulatory agency may consider the burden of the same side effects to be too high, given their view of the riskbenefit equation. A governmental or third-party payer might see the issue from an even different perspective, since a payer may not wish to bear the cost of the treatment or the cost of treating an adverse event.
It is not surprising that each group may take a different view of the same evidence. These pressures may lead to early decisions based on incomplete scientific data.


The goal of pharmacovigilance is to: Monitor the quality of drugs Identify the health risks involved in the administration of certain drugs Prevent harm to patients Research the efficacy of drugs


Pharmacovigilance helps save thousands of lives each year. By monitoring the adverse effects of drugs right from the lab to the pharmacy and then on for many years, pharmacovigilance keeps track of any drastic effects of drugs. This way, it prevents harm to patients using those drugs.


Pharmaceutical companies spend millions of dollars and a considerably long-time in developing new drugs. They again spend a lot of money in conducting clinical trials before the drugs are approved and launched in the market. But after all this, if there are adverse effects to the drugs, the company again loses millions of dollars in sales and litigations. Furthermore, the reputation of the company is also severely damaged. Pharmacovigilance monitors the development of the drug across various stages and assesses its effectiveness after its launch for many years. This way it may reduce the adverse risk from drugs, thereby aiding the drug manufacturers.


Regulatory agencies are increasingly proactive in seeking out potential safety issues with marketed drugs - you must be ready to respond quickly Political and social pressures have increased along with faster communication channels Failure to practice pharmacovigilance can lead to the suspension or withdrawal of license


Prevents Disasters Builds up customer confidence Ensures Compliance and retention Builds brand image


Health professionals should do their part by reporting untoward reactions to drugs used as this will serve as a trigger to conduct further investigations into safety issues As Malaysia ventures into producing biotech product, this will be even more critical The current scenario where new drugs are being registered faster, unregistered drugs are being brought in for compassionate use makes ADR reporting and monitoring even more relevant

Educate patients about the possibility of adverse reactions occurring

Advice them to inform you if it happens Help to solicit accurate information on the problem If you feel it is related to the product and that it is worthy of sharing the information, report to the NPCB



there is a problem with the quality or efficacy of a product, try get objective information product name, batch number and product sample Do not hesitate to report as you could be doing others a disservice by not doing so But bear in mind the NPCB can only take action based on facts NOT on emotions, whims and fancies of people All decisions made by the NPCB must take into account nature of the problem benefits and risks to patients willingness of the industry to overcome the issue



JAMA Therapie New EnglJ of Med Brit Med Journal The Lancet

Fast Comprehensive information

Expensive Low coverage



Pharmacoepidemiol ogy& Drug Safety Drug Safety Risk & Safety in Medicine Adverse Drug Reactions and Toxicology Reviews

Positive Advantages Fast High coverage Limitations Minimal detail Current Contents



-Quite fast -Some detail -High coverage

-Lack of detail -Difficult to search systematically-(Cost) -Reactions Weekly




Expert annotated review

Examples Meyler's Side Effects of Drugs Side Effects of Drugs Annual Adverse Drug Reaction Bulletin Prescrire Expert Opinion on Drug Safety Advantages -Assessment of significance -Easy access Limitations -Lack of detail -Not completely up-todate


Reference books
Martindale the extra Pharmacopoea
Meylers Side Effects of Drugs Pharmacovigilance from A-Z


Drug induced diseases Textbook of Adverse Drug Reactions(Davies, 1998) Avery's Drug Treatment(Speight, 1997) Drug Benefits and Risks(van Boxtel, Santoso, Edwards, 2002)


Reference books Addressing specific problem areas

A guide to drug eruptions(Bruinsma) Adverse Drug Interactions(Griffin, D'Arcy, 1997) Drugs in Pregnancy and Lactation(Briggs, Freeman,Yaffe, 1998) Drug-induced Ocular Side Effects(Fraunfelder, 2002) Adverse Effects of Herbal Drugs(De Smetet al 1992) Adverse Events Associated with childhood vaccines (Institof Med, 1994)

Responsibility for Drug-Induced Injury(Dukes, Mildred, Swartz, 1998)

Safety of Anaesthetic Drugs(Naguib, 1998)


References online
Micromedex Includes Martindale, PDR, Alternative Medicines and Index Nominum Merck Manual Includes: The Merck Manual of Diagnosis and Therapy SAM=Scientific American Medicine


Computerized literature screening

Advantages High coverage High specificity of search LimitationsRequires equipment & skill Lack of detail


Computerized literature screening

Medline Pubmedis using the MeSH(Medical Subject Headings) terminology. EMBASE Current Contents on CD Reactions Weekly on-line




Berita Ubat-Ubatan, Malaysia Folia Pharmacoterapeutica, Belgium Canadian Adverse Drug Reaction Newsletter TABU, Finland Drug Safety Newsletter, Ireland Information on Adverse Reactions to Drugs, Japan Adverse Drug Reaction News, Singapore PresciberUpdate, New Zealand Australian Adverse Reactions Bulletin Signals in Adverse Drug Reactions Monitoring, The Philippines ButlletGrocand many other regional bulletins, Spain Information frn Lkemedelsverket, Sweden Drug Information Bulletin, Tanzania


WHO Publications
National PharmacovigilanceSystems (Olsson, 1999)

Pharmacovigilance in Focus (Meyboom, 2001)

WHO Pharmaceuticals Newsletter WHO Drug Information Effective Communications in Pharmacovigilance Dialogue in Pharmacovigilance


Feedback given to registration holders

receive ADR report

report ADR
Pharmaceutical company Health professionals recommendations ADR form National ADR centre WHO

Drug Control Authority (DCA)

Malaysian ADR Advisory Committee (MADRAC)


Malaysian Adverse Drug Reactions Advisory Committee(MADRAC) National pharmaceutical control bureau


1 3 4 7 8 9 5

2 6 10 12


14 15

ADR Reports by Reporters

1400 1200
No. of Reports

1000 800 600 400 200 0 Government Doctors Others (Pharmacist, Dentist) GP/Private Specialist Reporters Company University

2004 2005 2006 2007

National Pharmaceutical Control Bureau