PHARMACOVIGILANCE

REPORTING METHODS&

SIGNAL DETECTION IN THE USA

Hafsa Hafeez, Alok Kumar, Emmanuel Egom, Muhammed Tanvir, Syed Ahmad Ali Shah

Academy of Applied Pharmaceutical Sciences, Toronto, Canada

Course: Global Clinical Research and Pharmacovigilance

Professor: Peivand Pirouzi

June 25, 2015

INTRODUCTION The process of informing about the adverse drug

reaction to the concerned individual/authority is known as reporting.

There are different methods used in Pharmacovigilance for reporting the adverse drug reactions.

PHARMACOVIGILANCE METHODS 1. Passive Surveillance

Spontaneous reporting Case Series

2. Stimulated Reporting 3. Active Surveillance

Sentinal Sites Drug Event Monitoring Registries

4. Comparative Observational Studies Cross-sectional Study (Survey) Case-control Study Cohort Study

5. Targeted Clinical Investigations 6. Descriptive Studies

Natural History of Disease

1. Passive Surveillance

SPONTANEOUS REPORTING

A report of an adverse drug reaction received directly from healthcare professionals/consumers/patients.

The report could be sent either to the nearest pharmacovigilance centre or to the manufacturer.

This is also known as voluntary reporting. Very important method of reporting. The number of spontaneous AE reports submitted

to FDA continues to grow, with over 600,000 reports in 2010, heading for over 700,000 in 2011.

ADVANTAGES Large population can be covered.

Hospital as well as outpatient data can be obtained.

Inexpensive

All medicines can be covered

Patient analysis is possible

                   

DISADVANTAGES Major weakness is under reporting (figures may vary

between countries as well as minor and major adverse reactions.

Overworked hospital staff may not consider reporting of ADR on a priority basis.

1. May not notice the ADR if symptoms are not serious

2. If symptoms are serious, they may not recognize them as the effect of a particular drug.

1.Passive Surveillance

Case Series

Series of case reports can provide evidence of an association between a drug and an adverse event, but they are generally more useful for generating hypotheses than for verifying an association between drug exposure and outcome.

2. Stimulated Reporting

Several methods have been used to encourage and facilitate reporting by health professionals in specific situations (e.g., in-hospital settings) for new products or for limited time periods. Such methods include on-line reporting of adverse events and systematic stimulation of reporting of adverse events based on a predesigned method. These methods have been shown to improve reporting, althought have their limitations as well.

3. Active Surveillance Active surveillance, in contrast to passive

surveillance, seeks to ascertain completely the number of adverse events via a continuous preorganized process. An example of active surveillance is the follow-up of patients treated with a particular drug through a risk management program. Patients who fill a prescription for this drug may be asked to complete a brief survey form and give permission for later contact. In general, it is more feasible to get comprehensive data on individual adverse event reports through an active surveillance system than through a passive reporting system.

Active Surveillance Sentinal Sites

Active surveillance can be achieved by reviewing medical records or interviewing patients and/or physicians in a sample of sentinel sites to ensure complete and accurate data on reported adverse events from these sites. The selected sites can provide information, such as data from specific patient subgroups, that would not be available in a passive spontaneous reporting system.

Specialized cohorts, networks There currently are a number of networks

established nationally and internationally focused on ascertainment and evaluation of adverse drug effects.

Such as the International Severe Adverse Events Consortium (iSAEC) and the Drug Induced Liver Injury Network (DILIN) focus on specific organ targets or patterns of adverse drug reactions. They have served as major sources of high quality AE reports as well as collaborative research efforts into the mechanisms, predisposition (pharmacogenomic and other), and pathogenesis of adverse drug reactions.

5. Targeted Clinical Investigations

When significant risks are identified from preapproval clinical trials, further clinical studies might be called for to evaluate the mechanism of action for the adverse reaction. In some instances, pharmacodynamic and pharmacokinetic studies might be conducted to determine whether a particular dosing instruction can put patients at an increased risk of adverse events.

6. Descriptive Studies Descriptive studies are an important

component of pharmacovigilance, although not for the detection or verification of adverse events associated with drug exposures. These studies are primarily used to obtain the background rate of outcome events and/or establish the prevalence of the use of drugs in specified populations.

6. Descriptive Studies

Natural History of Disease The science of epidemiology originally

focused on the natural history of disease, including the characteristics of diseased patients and the distribution of disease in selected populations, as well as estimating the incidence and prevalence of potential outcomes of interest. These outcomes of interest now include a description of disease treatment patterns and adverse events

PHARMACOVIGILANCE IN THE USA

FDA’s Center for Drug Evaluation and Research (CDER) is a consumer watchdog America’s healthcare system, specifically the Division of Pharmacovigilance

CDER regulates prescription drugs, generic drugs and over the counter drugs

Division of Pharmacovigilance •Evaluate the safety of drug and therapeutic biologic products •Advance public health by detecting and analyzing safety  signals from all available data sources, utilizing evidence‐ based methods

•Recommend appropriate regulatory actions, including labeling changes, Risk Evaluation and Mitigation Strategies  (REMS), etc. • Communicate relevant safety information

PV in USA Cont’d… Postmarketing Reports get to the FDA

through spontaneous (voluntary) reporting by patients, consumer, and healthcare professionals through FDA MedWatch (5% of total reports) and direct (mandatory) reporting from the manufacturers (95%)

Regulatory requirements mandate all ADRs received by the manufacturers to be reported to the FDA

PHARMACOVIGILANCE IN THE USA Cont’d… All ADRs are entered into the FDA Adverse

Event Reporting System (FAERS) Database. FDA Adverse Event Reporting System

• Computerized database • Spontaneous and Mandatory reports

• Contains human drug and therapeutic

biologic reports • > 7 million reports since 1969

• Nearly 1 million new reports in 2012

WHAT & WHEN TO REPORT Sometimes ADR may be difficult to detect/ important

information might be missing.

1. Collect the essential information and report the ADR as soon as you suspect that drug therapy has caused negative unintended effect.

2. Speed is another important factor.

GOOD REPORTING PRACTICE The report from the consumer should be crosschecked

with the health care practitioner familiar with the patient’s adverse event to obtain further medical information and to retrieve relevant medical records.

The adverse reaction report must include the following:

1) An identifiable patient.

2) A suspected health product.

3) An identifiable reporter.

4) A reaction.

Good Reporting Practice Cont’d…

The report should also include other information which are as follows:Concomitant medication, medical history, course of the event, suspect medication details, dechallenge/rechallenge, outcome of the event, lab details, etc.

Making the process of reporting user friendly.

It is always better to have fewer reports with high quality data than many reports with poor data quality.

In the USA, the MedWatch system allows you to enter the information mentioned above through a form online, mail or fax

MANDATORY REPORTING System under which manufacturer is required by law

to inform health authorities when a specified illness is diagnosed.

They are intended primarily for accountability, collect information about serious adverse events and disclose some information to the public.

Mandatory systems are intended to hold healthcare facilities accountable for preventable adverse events that result in serious injury or death.

Mandatory Reporting Cont’d…

In Canada reporting system consists of two components, reporting by manufacturers on a mandatory basis (regulatory requirement) and reporting by Canadian health professionals and patients/consumers on a voluntary basis.

The manufacturers in most of the countries submit all reports of ADR through QPPV (Qualified Person for Pharmacovigilance) to regulatory authority.

The problem of under-reporting to some extent can be addressed by making the process of reporting the adverse reaction mandatory by law.

Mandatory Reporting Cont’d…

While this may not achieve 100% compliance, it may prompt a significant number of health professionals to report who would not have otherwise reported.

Countries like France, Sweden, Austria, Norway, and Italy have this system for adverse reaction reporting by health professionals.

SIGNAL WHO Definition:

Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously (new information related to safety).

Mapping is based on spontaneous reports in the safety database.

SIGNAL

Usually more than one report is required to generate a signal

It is a matter of looking for patterns or clusters of reports that stand out from the background

SIGNAL DETECTION Speed of SD depends on the following factors:

1. Number of users

2. Frequency of ADR

3. Reporting rate

4. Quality of documentation

Automated SD has helped in detecting signals early. SD has an important role to play in enhancing safety

of the drug. It is an integral part of every adverse event reporting

system.

TYPES OF SIGNALS Quantitative (depending on number of case reports)

Qualitative

1. Consistency of data

2. Exposure – response relationship

3. Biological plausibility (pathological and pharmacological mechanisms)

4. Experimental findings

5. Analogy (previous experience with this drug)

6. Nature and quality of data

Sources of Possible Safety Signals in the USA Routine pharmacovigilance 

– FAERS– Datamining– Periodic Safety Update Reports

Study results  Medical literature Media

New Drug Application (NDA) safety database Outside inquiry Foreign Regulatory Agencies Others

SIGNAL VALIDATION & STRENTHENINGValidation Get more information from reporter Take opinion from health professionals/specialists Causality assessment

Strengthening Get more information from literature, manufacturer,

database (international database), reports from clinical trials.

Analogy with other related drugs.

“Absence of supporting data does not indicate that it was a false signal.”

THANK YOU

References Fine, A. (2013). Introduction to Post marketing Drug Safety

Surveillance: Pharmacovigilance in FDA/CDER (PowerPoint slides), Retreived from: http://www.fda.gov/downloads/AboutFDA/WorkingatFDA/FellowshipInternshipGraduateFacultyPrograms/PharmacyStudentExperientialProgramCDER/UCM340626.pdf

FDA Science Board (2011). FDA Science Board Subcommittee: Review of the FDA/CDER Pharmacovigilance Program, Retreived from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ScienceBoardtotheFoodandDrugAdministration/UCM276888.pdf

Cobert, Barton L, and Barton L Cobert. Cobert's Manual Of Drug Safety And Pharmacovigilance. Sudbury, Mass.: Jones

& Bartlett Learning, 2012.