Pharmacovigilance

PHARMACOVIGILANCE

Dr. P.Naina Mohamed PhDPharmacologist

INTRODUCTION

Pharmacoepidemiology is the study of effects of drugs in

large population.

Pharmacovigilance is a branch of Pharmacoepidemiology

and is restricted to the study of adverse effects of drugs.

Pharmacovigilance is a scientific discipline concerned with

the collection, detection, assessment, monitoring, and

prevention of adverse effects of pharmaceutical products.

Pharmacovigilance

Pharmakon (Greek) -Drug

Vigilare (Latin) – To keep watch

AIMS OF PHARMACOVIGILANCE

Identification and quantification of previously unrecognized ADRs.

Identification of patient related risk factors of ADRs such as dose, age, gender, and underlying disease.

Continued monitoring of the safety of a product throughout the duration of its use to ensure that its risks and benefits remain acceptable.

Comparing the ADR profile with same therapeutic class drugs.

Detection of inappropriate prescription and administration.

Further elucidation of a product's pharmacological / toxicological properties and the mechanism by which it produces ADRs.

Detection of significant drug-drug interactions between new products and agents already established on the market.

Communication of appropriate information to healthcare professionals.

CLASSIFICATION OF ADRS

Adverse drug reactions (ADRs) are frequently

classified as ‘type A’ and ‘type B’ reactions. An

extended version of this classification system is

as follows…

Adverse Drug Reactions

(ADRs)

Type A (Augmented)

reactions

Pharmacological Pathological Genotoxic

Type B (Bizarre) reactions

Type C (Chronic) reactions

Type D (Delayed) reactions

Type E (End-of-

use) reactions

TYPE A (AUGMENTED) REACTIONS

Type A (Augmented) reactions may be caused by exaggeration of therapeutic effect due to overdose (Pharmacological) or disease condition like Hepatic and Renal failure (Pathological) or injury to DNA (Genotoxic) by therapeutic agents.

They are predictable from the drug’s pharmacology.

They are preventable.

They are usually dose-dependent.

They are readily reversible on drug withdrawal or even simply after dose reduction.

Type A reactions are more common than the type B reactions and they account for over 80% of all reactions.

They have high morbidity and low mortality

Examples:

Warfarin induced Bleeding.

Sulfonylureas associated Hypoglycemia.

Respiratory depression with Opioids.

TYPE B (BIZARRE) REACTIONS

Type B (Bizarre) reactions or Side effects occurs not through

therapeutic mechanism.

They are idiosyncratic or immunologic reactions.

These are less common.

They cannot be predicted from the known pharmacological

actions of the drug.

They are not dose dependent.

Examples:

Anaphylaxis with a Penicillin.

Hypersensitivity reactions, such as serious skin

reactions with Lamotrigine.

TYPE C, D & E REACTIONS

Type C (Chronic) or ‘continuing’ reactions, persist relatively for a long time.

Example: Biphosphonates induce Osteonecrosis of the jaw.

Type D (Delayed) reactions, become apparent some time after the use of a medicine. The timing of these may make them more difficult to detect.

Example: Lomustine may cause Leucopenia, after six weeks of tretment.

Type E (End-of-use) reactions, are associated with the withdrawal of a medicine.

Example: Benzodiazepines may cause insomnia, anxiety and perceptual disturbances following their withdrawal.

PHARMACOVIGILANCE METHODOLOGIES

Passive drug Surveillance methodologies

Spontaneous reports

Active drug surveillance methodologies

Enhanced spontaneous reporting

Stimulated reporting through solicited reports

Designated sentinel sites (sometimes referred to as geographic surveillance)

Ad hoc assembly of a cohort of patients

Systematic assembly of a cohort of patients

Case-controlled surveillance (also called disease registries or disease-specific surveillance)

Population-based surveillance

Large automated multipurpose databases

PASSIVE DRUG SURVEILLANCE

Collection of adverse events that come into the company from

all of its offices and any departments or routes, is known as

Passive surveillance.

Passive surveillance may be done usually as spontaneous

reports.

Adverse events must be reported to the regulatory agencies

according to established rules and policies.

Advantages of passive surveillance :

Covers a large population at very low cost.

Includes all of the company's drugs being used.

Detects rare events as a signal.

Helps to identify the risk factors.

Creates a hypothesis that can be tested with more active

methods

LIMITATIONS OF PASSIVE SURVEILLANCE

Limitations of passive surveillance :

Due to physicians' lack of motivation, lack of knowledge of the procedures to follow, and concern about their own liability and patient confidentiality issues, the amount of reports received are generally a small percentage of those that occur.

Reports may be received much later than the occurrence, and follow-up discussions to obtain more complete data will be limited.

Bias exists in the selection of cases that are reported.

Data reported are incomplete and usually not well validated.

Data submitted are often difficult to interpret.

Limitations of passive surveillance (from the company's perspective):

It is usually difficult to know if a report is a signal.

It is difficult to know the real numerator or denominator of the event reported.

Professionals tend to focus on bad news.

The attribution of the adverse event to a specific drug is often weak.

Data submitted are usually incomplete and difficult to interpret.

If the media or medical literature has focused on a specific event, there will be an exaggerated number of those events reported.

ACTIVE DRUG SURVEILLANCE METHODOLOGIES

Reasons to consider Active Surveillance:

This is a useful method to capture early data on

drug use after a launch.

One will learn bad news early, and this will allow the

company to react, plan, and obtain a more

complete understanding of the issue/problem.

Unanticipated benefits may be learned.

Passive surveillance techniques are insufficient

today to meet the more rigorous standards of safety

surveillance that have evolved.

ENHANCED SPONTANEOUS REPORTING

The issue of drug alert newsletters or bulletins that

report a potential problem and seek experiences of

other physicians by the company is termed as

Enhanced Spontaneous Reporting.

A case report of an adverse event published in a

medical journal also serves to understand the

incidence of the event.

The use of the MedWatch system to stimulate

reporting is another means of enhancing

spontaneous reporting with a toll-free telephone

number placed.

STIMULATED REPORTING THROUGH SOLICITED

REPORTS

Companies usually have arrangements with IMS (a company that obtains data on drug utilization) to learn about the uses and extent of how much their drugs are used in various settings (e.g., hospitals, retail pharmacies).

The company's follow-up may reveal whether a patient's discontinuation was due to an adverse event or to other reasons.

With the data obtained from all sources, a company will begin to create its own internal warehouse of data to confirm or deny the occurrence of new adverse events brought to the company by regulators or others.

These data are used to assess whether certain characteristics are or are not risk factors for adverse events, whether drug-drug interactions are occurring, and to conduct many other analyses.

DESIGNATED SENTINEL SITES

The company or a regulatory body itself designates the sites

to be its sentinel sites.

These sites may be in selected hospitals or clinics chosen for

their expertise and large number of patients whose treatments

would be of particular interest.

Sites could be chosen on a geographic basis to monitor the

incidence and prevalence of infectious disease, number of

medical or medication errors, or adverse events.

Other roles of sentinel sites can be to examine various

aspects of physician prescribing behavior, examine aspects of

institutional compliance with use of the company's product,

and conduct various research projects on the safety and

surveillance program itself (e.g., referral patterns to the

sentinel site).

EXPECTED ADVANTAGES OF THE SENTINEL SITE

MODEL

Previously unrecognized serious adverse events would likely be referred to specialists at the sentinel site.

The proportion of cases seen at the sentinel site would be higher than those seen in other settings.

Information obtained would be more valid and complete than data received from using other methods.

Signals would be more rapidly identified and followed-up than with other methods.

False-positive case reports of serious adverse events would be readily identified at the site.

Causality would be carefully assessed, and the resulting data would be more valid.

This approach would enhance the company's ability to learn about its product in a cost- and time-effective manner.

LIMITATIONS OF THE SENTINEL SITE MODEL

There will be too little power to detect rare events, particularly for drugs used to treat only a few or a moderate number of patients.

Referrals to specialty programs, such as liver transplant centers, may mean that sentinel sites will miss those cases of hepatotoxicity it is hoping to observe.

Sentinel sites that look at a wide variety of drugs for a company may be too general and may miss various aspects/adverse events of specific drugs.

A sentinel system that is general could be set up as Centers of Excellence, and their nonspecific approach would probably identify many false-positive safety signals that would lead the company to do unnecessary trials.

The signal-to-noise ratio using general sites may obviate the benefits they offer.

AD HOC ASSEMBLY OF A COHORT OF PATIENTS

This is a traditional model where a large number of

patients (e.g., 10,000) are enrolled in a trial to learn

about all of the adverse events they experience in

taking the company's drug.

This is a signal detection activity.

It was popular in the early 1980s to collect data on

the first 10,000 or so patients who used a newly

approved drug to evaluate the adverse events.

Very little information on adverse events came from

these trials, and this approach was generally

abandoned.

CASE-CONTROL SURVEILLANCE / OBSERVATIONAL

TRIALS

A case-control surveillance/observational trial involves all cases of various adverse outcomes that are collected and all drug exposure reascertainment through interviews or medical records.

This is also called an outcome registry because it focuses on a specific adverse outcome of public policy interest (e.g., birth defects).

Observational trials are noninterventional.

In these trials an investigator “observes and evaluates results of ongoing medical care without ‘controlling’ the therapy beyond normal medical practice.”

These trials do require a protocol, and almost all observational trials must be reviewed by Institutional Review Boards/Ethics Committees.

Other types of comparative observational trials include cross-sectional trials and cohort trials, both retrospective and prospective.

POPULATION-BASED SURVEILLANCE

In this methodology, an entire population is monitored for both positive and negative signals.

These are longitudinal trials and are often conducted over many years or even decades.

The most well known of these is the US Framingham Study, and others in Finland and Sweden have been in place for many years.

The Framingham Study focused on all people in a small Massachusetts town, and the US Nurses Study focused on nurses and later added other healthcare personnel.

These trials were not originally designed or initiated for pharmaceutical or device products or trials, but for general medical purposes.

LARGE AUTOMATED MULTIPURPOSE DATABASES

In healthcare groups of United States, Canada and

Europe, there are linkages of electronic medical records

with accounting and billing systems.

These databases permit linking pharmacy or prescribing

records with information on medical outcomes.

Large automated multipurpose databases may be

queried for signals of any problem that occurs at a

higher than expected frequency and is associated with a

drug.

Large pharmaceutical companies often use this method

to test a hypothesis or to confirm a purported signal.

IMPORTANCE OF IMPLEMENTING

PHARMACOVIGILANCE

The effect of medicines might be affected by presence of many

different diseases, drugs, diets and traditional and herbal remedies.

It is essential that a monitoring system for the safety of medicines is

supported by doctors, pharmacists, nurses and other health

professionals in the country to prevent unnecessary suffering by

patients and financial loss.

Adverse reactions should be reported on a daily basis through the

Drug Regulatory Authority’s national pharmacovigilance programme.

Systematic safety monitoring is needed to identify previously

recognized and unrecognized adverse drug reactions of medicines in

the postmarketing period.

Postmarketing surveillance involves the ongoing processes of risk

identification, risk assessment, and risk mitigation.

The goal is always the accurate assessment of the benefit versus the

risk of a product in the populations who receive it.

ROLES OF THE PHARMACIST

The pharmacists should…

Educate other healthcare professionals about prevention, detection and reporting of ADRs.

Develop policies and procedures for the ADR-monitoring and reporting program.

Describe the responsibilities and interactions of pharmacists, physicians, nurses, risk managers, and other health professionals in the ADR program.

Perform patient counseling on ADRs.

Identify the drugs and patients at high risk for being involved in ADRs.

Report serious ADRs to the FDA or the manufacturer (or both).

ROLES OF PRESCRIBERS

All prescribers need to be aware of ADR reporting and its important.

Consider the drug therapy is really necessary.

Any new symptom(s) experienced by the patients should be considered as ADR.

Check the patient’s history of Drug allergy.

Check about other medications (OTC drugs, chronic medications, etc) the patient is taking.

Explain the patients about risk/benefit of the drugs.

Counsel the patients about proper use of medicines.

Watch for ADRs and report them immediately.

PREVENTION OF ADRS

Some ADRs are unavoidable and cannot be prevented.

However, most ADRs can be prevented by following the basic principles of rational use of

medicines as follows:

Use few drugs, whenever possible.

Use drug that well known.

Do not change therapy from known drugs to unfamiliar one without good reasons.

Use text books and other reference materials providing information on drug

reactions and interactions.

Take extra care while prescribing drugs known to exhibit a large variety of

interactions and adverse reactions (anticoagulants, hypoglycemic, and drug affecting

the CNS) with careful monitoring of patients with such reactions.

Beware of the interaction of drugs with certain food stuffs, alcohol, etc.

Review all the drugs (including Over the counter, herbal preparations ) used by

patients regularly.

Be particularly careful when prescribing to children, the elderly, the pregnant and

nursing women, the seriously ill and patients with hepatic and renal diseases.

Think of adverse drug reaction, when the patients show signs or symptoms not

clearly explained by the course of their illness.

Consider stopping the drug or reduce the dosage as soon as the ADR is identified.

CONCLUSION

Pharmacovigilance and risk management are an

essential part of pharmaceutical product

development and commercialization.

Pharmacovigilance and risk management must

extend throughout the product’s life cycle to identify

rare adverse events.

Pharmacists and Prescribers play important roles in

reporting of ADRs.

REFERENCES

Pharmacovigilance, 2nd Edition

Ronald D. Mann, Elizabeth B. Andrews

An Introduction to Pharmacovigilance

Patrick Waller

Cobert’s Manual of Drug safety and

Pharmacovigilance, 2nd edn

Barton Cobert

Guide to Drug Development: A Comprehensive

Review and Assessment, 1st Edition

Bert Spilker PhD, MD

Global Clinical Trials Playbook, 1st Edition

Menghis Bairu, Richard Chin

REFERENCES

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073107.pdf

http://www.who.int/medicines/areas/quality_safety/safety_efficacy/S.AfricaDraftGuidelines.pdf

http://ec.europa.eu/health/human-use/pharmacovigilance/index_en.htm

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000258.jsp