INFORMATION RESOURCES IN

PHARMACOVIGILANCE
DRUG INFORMATION RESOURCES
SPECIALISED RESOURCES FOR ADRS
DRUG INFORMATION RESOURCES
The quantity of medical information and medical literature available is growing at an astounding
rate.
The technology by which this information can be accessed is also improving exponentially.
Pharmacists are being asked daily to provide responses to numerous drug information requests
for a variety of people.
It is tempting just to select the easiest, most familiar resources to find information; however, by
doing that there is the possibility of missing new resources or limiting the comprehensiveness of
the information found.
Generally, the best method to find information includes a stepwise approach moving first
through tertiary (e.g., textbooks, full-text databases, and review articles), then secondary (e.g.,
indexing or abstracting service), and finally primary (e.g., clinical studies) literature.
DRUG INFORMATION RESOURCES
The tertiary sources will provide the practitioner with general information needed to familiarize
the reader with the topic.
If this information is not recent or comprehensive enough, a secondary database may be
employed to direct the reader to review primary literature articles that might provide more
insight on the topic.
Primary literature often provides the most recent and in-depth information about a topic, and
allows the reader to analyze and critique the study methodology to determine if the conclusions
are valid.
Sometimes it may be necessary to consult news reports or other Internet sites to get
background information before beginning the searching process for a request.
Also, other resources, including experts or specialists in particular areas of practice, may need to
be consulted.
TERTIARY RESOURCES
Tertiary resources consist of textbooks, compendia, review articles in journals, and other general
information, such as may be found on the Internet.
These references may often serve as an initial place to identify information due to the fact that
they provide a fairly complete and concise overview of information available on a specific topic.
These resources are convenient, easy to use, and familiar to most practitioners.
Most of the information needed by a practitioner can be found in these sources, making these
excellent first-line resources when dealing with a drug information question.
TERTIARY RESOURCES
The major drawback to tertiary resources, however, is the lag time associated with publication,
resulting in less current information.
Medical information changes so rapidly that it is possible that information may be out of date
before it is even published.
It is also possible that information in a tertiary text may be incomplete due either to space
limitations of the book or incomplete literature searches by the author.
Other problem that can be seen with tertiary information include errors in transcription, human
bias, incorrect interpretation of information, or a lack of expertise by authors.
For these reasons, readers must judge the quality of tertiary references.
SECONDARY RESOURCES
Secondary literature refers to references that either index or abstract the primary literature with
the goal of directing the user to the primary literature.
The two terms, indexing and abstracting, differ slightly.
Indexing consists of providing bibliographic citation information (e.g., title, author, and citation
of the article), while abstracting also includes a brief description (or abstract) of the information
provided by the article or resource cited.
Various systems will index or abstract literature from different journals, meetings, or
publications, therefore, in order to perform a comprehensive search, different databases must
be used.
The vast majority of secondary resources are utilized primarily in an electronic format, although
some may still have a print form.
SECONDARY RESOURCES
PAPER RESOURCE
Occasionally a paper resource may be used because it is less costly than an electronic database.
Using a paper resource will often require more time than the electronic formats, due to the
need to look at multiple editions and indexes (possibly an annual or quarterly listing).
There is an additional disadvantage in that the printed sources can be searched by only one user
at a time.
An advantage to printed resources is their use for browsing for new information.
SECONDARY RESOURCES
ELECTRONIC DATABASE
Electronic databases offer some advantages over print listings.
Notably, for online listings, the more frequent updating of listings and information is very
important.
In searching most electronic databases, a user will follow a similar search strategy, with small
changes to reflect differences in database systems.
There are several challenges in searching secondary database systems.
Systems do not index all terms in the same manner therefore it is necessary to determine what
terms a database is using to conduct a successful search.
Most computerized databases also include a free-text search option, which is very useful when
the defined index terms are not identifying relevant data.
SECONDARY RESOURCES
The need to utilize a variety of terms for search strategy is illustrated in the following sample question
“Is clonidine effective in the treatment of attention deficit hyperactivity disorder (ADHD) in
adolescents?”
It is first important to identify the key terms.
These terms might include clonidine, ADHD, and adolescents.
However, some databases may not recognize the term adolescent and instead may require use of the
term paediatric or child.
Additionally, the use of the term paediatric may just refer to the medical specialty in some resources,
rather than the paediatric patient population.
Therefore, it is important to recognize that different databases may require different search terms to
be used.
Also, the name of the disease state, attention deficit hyperactivity disorder, has changed over time
and so it may be necessary to use other terms, such as attention deficit disorder.
SECONDARY RESOURCES
Examples of Secondary Resources
ANTI-INFECTIVES TODAY: Adis International, <<www.adis.com>>
BIOLOGIC ABSTRACTS/BIOSIS PREVIEWS: Thompson Medical, <<www.biosis.org>>
CANCER TODAY: Adis International, <<www.adis.com>>
CANCERLIT: National Cancer Institute, <<http://www.cancer.gov/>>
THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS: Cochrane Library, <<www.cochrane.org>>
EMBASE: Elsevier, <<www.embase.com>>
GOOGLE SCHOLAR: Google, <<scholar.google.com>>
MEDLINE®: National Library of Medicine, <<www.nlm.nih.gov>>
REACTIONS WEEKLY: Adis International, <<www.adis.com>>
PRIMARY RESOURCES
Primary literature consists of clinical research studies and reports, both published and
unpublished.
Not all literature published in a journal is classified as primary literature, for example, review
articles or editorials are not primary literature.
There are several types of publications considered primary, including controlled trials, cohort
studies, case series, and case reports.
PRIMARY RESOURCES
Advantages of the use of primary literature include access to detailed information about a topic
and the ability to personally assess the utility and validity of study results.
Additionally, primary literature tends to be more recent than tertiary or secondary literature.
However, there are several disadvantages of using primary literature alone.
These disadvantages include misleading conclusions based on only one trial without the context
of other researches, the need to have good skills in medial-literature evaluation, and the time
needed to evaluate the large volume of literature available.
SPECIALISED RESOURCES FOR ADRS
Adverse event (AE) data are collected all over the world by many people and groups.
There is little standardization in the way they are collected, how they are measured and graded,
how they are stored, and how they are used.
Some of the data are collected as a matter of public health, and some are collected by
pharmaceutical companies or other companies or nongovernmental organizations that process
the data and make available or sell them to others.
In theory, with the International Conference on Harmonization (ICH), Council for International
Organizations of Medical Sciences (CIOMS), Medical Dictionary for Regulatory Activities
(MedDRA), we are moving toward improved standardization and use of these data.
AERS
The FDA has a large amount of data stored in four publicly accessible databases of primarily
post-marketing safety data as well as other proprietary databases containing clinical trial
information.
The FDA drug database for all approved drug and therapeutic biologic products is the Adverse
Event Reporting System (AERS)
AERS (Web Resource 8-1) collects information about AEs, medication errors, and product
problems on marketed drug and therapeutic biologic products.
It is ICH E2B compliant and MedDRA is used for coding.
AERS
Quarterly (noncumulative) data files since January 2004 are available under the United States
Freedom of Information Act for downloading as zipped SGML or ASCII files.
Data include information on patient demographics, the drug(s) reported, the adverse
reaction(s), patient outcome, and the source of the reports.
The actual files can be downloaded directly.
The data can be downloaded and manipulated (though not easily), and various companies offer
services that include periodic updates, data searches, or repackaging of the data in a more user-
friendly form.
The database cannot be searched directly.
AERS
There is a variable lag of several months between AEs’ being reported to the FDA and their
making it into the
quarterly data files.
Should further information be desired after reviewing the data from the quarterly report, the
full MedWatch form (anonymized to protect the reporter and patient) can be obtained using the
unique identification number assigned to each case by the FDA.
Data can be obtained directly from the FDA under the Freedom of Information Act (Web
Resource 8-2) or from private companies.
Using the latter ensures the anonymity of the requester, and some companies use these services
to obtain information on their competitors’ products.
AERS
This database is rather large, with some 4 million cases, and is growing by roughly half a million cases
per year.
About 35,000 are received directly by the FDA each year with the remainder from industry.
Of the industry reports, about 300,000 are 15-day expedited reports and the rest are from periodic
reporting.
AERS contains primarily post-marketing data from prescription drugs, biologics, and over-the-counter
drugs with an approved NDA sold in the United States, but it also contains some foreign reports of
AEs for these drugs.
Most of the industry reports are sent electronically, though paper reports (MedWatch 3500A forms)
are still accepted at this writing.
The data vary in quality, ranging from full due diligence inquiries and follow-ups with complementary
data (laboratory reports, electrocardiograms, etc.) to lay consumer reports not validated by a medical
professional.
CLINICAL TRIAL DATA
There are few clinical trial data in the FDA AERS database.
The clinical trial data are proprietary and are generally not available.
Some clinical trial safety data can be found in Summary Basis of Approval documents that the
FDA sometimes releases after a drug is approved.
They are not easily found on the website and need to be searched for using the search box.
VIGIBASE
Vigibase is the AE database that the UMC maintains on behalf of the World Health Organization.
The database has more than 5 million AE case reports from 90 countries and is growing by nearly half
a million cases a year.
The data are supplied by national health authorities.
Much of the data are from the United States and are supplied by the FDA.
The UMC does not review or assess the individual cases put into the database, but it does
pharmacovigilance analyses and signaling.
Not all of the supplying countries allow their data to be released.
The database does not contain all the data found in the national databases (e.g., FDA’s AERS) but
rather contains extracts.
The UMC notes that the data are “available to anyone with a health professional degree-level
education (physician, dentist, nurse, pharmacist).”
The database contains information on drugs as well as OTC products and herbals.
EMEA EUDRAVIGILANCE DATABASE
EudraVigilance is a data-processing network and management system for reporting and storing
ADRs from clinical trials and in the postmarketing setting for products in the European Economic
Area (EEA). It was launched in 2001.
EudraVigilance is used for the electronic exchange of SAEs among the European Medicines
Agency (EMA), member states’ health authorities, MA holders, and sponsors of clinical trials in
the EEA; detection of possible safety signals; and the continuous monitoring and evaluation of
potential safety issues.
There are two modules: The EudraVigilance Clinical Trial Module (EVCTM) and the Post-
Authorisation Module (EVPM).
The database is maintained by the EMA in London.
MOTHERISK
Motherisk is a clinical, research, and teaching program affiliated with the University of Toronto
(Canada).
They have many services and much valuable information on pregnancy aimed at mothers,
families, and healthcare practitioners (Web Resource 8-12).
In particular, in regard to drug safety, they have a website with information about the use of
drugs in pregnancy (Web Resource 8-13).
Their comments are based on their reviews of data from around the world.
It is their view that “it is now clear that there are many drugs that are safe for use in pregnancy.”
They have comments and reviews of many specific drugs as well as information on herbals and
breast-feeding and drugs.
MHRA
The United Kingdom health agency has information from its Yellow Card Scheme available as
Drug Analysis Prints (DAPs).
DAPs contain complete listings of all suspected ADRs from the Yellow Card Scheme.
They include both healthcare professional and consumer reports for a particular medicine.
Products are listed by ingredient on the MHRA DAP Web page.
The information is updated periodically.
These listings are useful for signaling and are available as PDF files.
GENERAL PRACTICE RESEARCH DATABASE
(GPRD)
The GPRD (formerly called VAMP) is a large database of anonymized longitudinal medical
records from primary care practitioners linked with other healthcare data.
Currently data are collected on more than 4 million active patients of research standard from
around 500 primary care practices throughout the United Kingdom.
It is used for drug safety, clinical epidemiology, pharmacoeconomics, and many other subjects in
healthcare.
Data can be obtained via the internet or on CD-ROM.
Linked GPRD is only available through the GPRD Division of the MHRA in London and is the ONLY
source of regularly updated, validated GPRD data.
It is controlled and managed by the United Kingdom MHRA.
DRUG UTILIZATION
NEED, TYPES OF DRUG UTILIZATION STUDIES
DRUG USE EVALUATION
What is drug utilization research??
The development of drug utilization research was sparked by initiatives taken in Northern
Europe and the United Kingdom in the mid- 1960s.
The pioneering work of Arthur Engel in Sweden and Pieter Siderius in Holland alerted many
investigators to the importance of comparing drug use between different countries and regions.
Their demonstration of the remarkable differences in the sales of antibiotics in six European
countries between 1966 and 1967 inspired WHO to organize its first meeting on «Drug
consumption» in Oslo in 1969.
This led to the constitution of the WHO European Drug Utilization Research Group (DURG).
The pioneers of this research understood that a correct interpretation of data on drug utilization
requires investigations at the patient level.
What is drug utilization research??
It became clear that we need to know the answers to the following questions:
• why drugs are prescribed;
• who the prescribers are;
• for whom the prescribers prescribe;
• whether patients take their medicines correctly;
• what the benefits and risks of the drugs are.
The ultimate goal of drug utilization research must be to assess whether drug therapy is rational
or not.
What is drug utilization research??
Drug utilization research was defined by WHO in 1977 as «the marketing, distribution,
prescription, and use of drugs in a society, with special emphasis on the resulting medical, social
and economic consequences».
Epidemiology has been defined as «the study of the distribution and determinants of health
related states and events in the population, and the application of this study to control of health
problems».
Pharmacoepidemiology applies epidemiological methods to studies of the clinical use of drugs
in populations. A modern definition of pharmacoepidemiology is: «the study of the use and
effects/side-effects of drugs in large numbers of people with the purpose of supporting the
rational and cost-effective use of drugs in the population thereby improving health outcomes».
Pharmaco-surveillance and pharmacovigilance are terms used to refer to the monitoring of
drug safety, for example, by means of spontaneous adverse-effect reporting systems, case-
control and cohort studies.
What is drug utilization research??
Pharmacoepidemiology may be drug-oriented, emphasizing the safety and effectiveness of
individual drugs or groups of drugs, or utilization oriented aiming to improve the quality of drug
therapy through pedagogic (educational) intervention.
Drug utilization research may also be divided into descriptive and analytical studies.
The emphasis of the former has been to describe patterns of drug utilization and to identify
problems deserving more detailed studies.
Analytical studies try to link data on drug utilization to figures on morbidity, outcome of
treatment and quality of care with the ultimate goal of assessing whether drug therapy is
rational or not.
Sophisticated utilization-oriented pharmacoepidemiology may focus on the drug (e.g. dose-
effect and concentration-effect relationships), the prescriber (e.g. quality indices of the
prescription), or the patient (e.g. selection of drug and dose, and comparisons of kidney
function, drug metabolic phenotype/genotype, age, etc.).
What is drug utilization research??
Together, drug utilization research and pharmacoepidemiology may provide insights into the
following aspects of drug use and drug prescribing.
• Pattern of use
• Quality of use
• Determinants of use
• Outcomes of use
Drug utilization research also provides insight into the efficiency of drug use, i.e. whether a
certain drug therapy provides value for money and the results of such research can be used to
help to set priorities for the rational allocation of health care budgets.
Why drug utilization research?
The principal aim of drug utilization research is to facilitate the rational use of drugs in
populations.
For the individual patient, the rational use of a drug implies the prescription of a well-
documented drug at an optimal dose, together with the correct information, at an affordable
price.
Without a knowledge of how drugs are being prescribed and used, it is difficult to initiate a
discussion on rational drug use or to suggest measures to improve prescribing habits.
Why drug utilization research?
DESCRIPTION OF DRUG USE PATTERNS
Drug utilization research can increase our understanding of how drugs are being used as follows.
• It can be used to estimate the numbers of patients exposed to specified drugs within a given
time period.
• It can describe the extent of use at a certain moment and/or in a certain area (e.g. in a
country, region, community or hospital).
• Researchers can estimate (e.g. on the basis of epidemiological data on a disease) to what
extent drugs are properly used, overused or underused.
• It can determine the pattern or profile of drug use and the extent to which alternative drugs
are being used to treat particular conditions.
• It can be used to compare the observed patterns of drug use for the treatment of a certain
disease with current recommendations or guidelines.
Why drug utilization research?
DESCRIPTION OF DRUG USE PATTERNS
• Drug utilization data can be fed back to prescribers. This is particularly useful when the drug
prescribing by a particular individual can be compared with some form of «gold standard» or
best practice, and with the average prescriptions in the relevant country, region or area.
• The number of case reports about a drug problem or adverse effects can be related to the
number of patients exposed to the drug to assess the potential magnitude of the problem. If it is
possible to detect that the reaction is more common in a certain age group, in certain conditions
or at a given dose level, improving the information on indications, contraindications and
appropriate dosages may be sufficient to ensure safer use and avoid withdrawal of the drug
from the market.
Why drug utilization research?
EARLY SIGNALS OF IRRATIONAL USE OF DRUGS
• Drug utilization research may generate hypotheses that set the agenda for further
investigations as outlined below, and thus avoid prolonged irrational use of drugs.
• Drug utilization patterns and costs between different regions or at different times may be
compared. Hypotheses can be generated to form the basis for investigations of the reasons for,
and health implications of, the differences found. Geographical differences and changes in drug
use over time may have medical, social and economic implications both for the individual
patient and for society, and should therefore be identified, explained and, when necessary
corrected.
• The observed patterns of drug use can be compared with the current recommendations and
guidelines for the treatment of a certain disease. Hypotheses can then be generated to
determine whether discrepancies represent less than optimal practice, whether pedagogic
interventions (education) are required or whether the guidelines should be reviewed in the light
of actual practice. These hypotheses should apply to both under use and over use of drugs.
Why drug utilization research?
INTERVENTIONS TO IMPROVE DRUG USE - FOLLOW-UP
Drug utilization research undertaken in the following ways may enable us to assess whether
interventions intended to improve drug use have had the desired impact.
• The effects of measures taken to ameliorate undesirable patterns of drug use (e.g. provision of
regional or local formularies, information campaigns and regulatory policies) should be
monitored and evaluated. The researchers should bear in mind that prescribers may have
switched to other drugs that are equally undesirable. These potential alternative drugs should
be included in the survey to assess the full impact of the measure.
• The extent to which the promotional activities of the pharmaceutical industry and the
educational activities of the society affect the patterns of drug use should be assessed.
Why drug utilization research?
QUALITY CONTROL OF DRUG USE
Drug use should be controlled according to a quality control cycle that offers a systematic
framework for continuous quality improvement.
TYPES OF DRUG UTILIZATION STUDY
Drug utilization studies can be targeted towards any of the following links in the drug-use chain:
– the systems and structures surrounding drug use (e.g. how drugs are ordered, delivered and
administered in a hospital or health care facility);
– the processes of drug use (e.g. what drugs are used and how they are used and does their use
comply with the relevant criteria, guidelines or restrictions); and
– the outcomes of drug use (e.g. efficacy, adverse drug reactions and the use of resources such
as drugs, laboratory tests, hospital beds or procedures).
TYPES OF DRUG UTILIZATION STUDY
Cross-sectional studies
Cross-sectional data provide a «snapshot» of drug use at a particular time (e.g. over a year, a
month or a day). Such studies might be used for making comparisons with similar data collected
over the same period in a different country, health facility or ward, and could be drug-, problem-
, indication, prescriber- or patient-based.
Alternatively, a cross-sectional study can be carried out before and after an educational or other
intervention.
Studies can simply measure drug use, or can be criterion-based to assess drug use in relation to
guidelines or restrictions.
TYPES OF DRUG UTILIZATION STUDY
Longitudinal studies
Public health authorities are often interested in trends in drug use, and longitudinal data are
required for this purpose.
Drug-based longitudinal data can be on total drug use as obtained through a claims database, or
the data may be based on a statistically valid sample of pharmacies or medical practices.
Longitudinal data are often obtained from repeated cross-sectional surveys (e.g. IMS
(Intercontinental Medical Statistics) practice-based data are of this type).
Data collection is continuous, but the practitioners surveyed, and therefore the patients, are
continually changing.
Such data give information about overall trends, but not about prescribing trends for individual
practitioners or practices.
TYPES OF DRUG UTILIZATION STUDY
Continuous longitudinal studies
In some cases continuous longitudinal data at the individual practitioner and patient level can be
obtained.
Claims databases are often able to follow individual patients using a unique (but anonymous)
identifier.
These data can provide information about concordance with treatment based on the period between
prescriptions, co-prescribing, duration of treatment, prescribed daily doses (PDDs) and so on.
As electronic prescribing becomes more common, databases are being developed to provide
continuous longitudinal data comprising full medical and prescribing information at the individual
patient level.
Such databases are very powerful, and can address a range of issues including reasons for changes in
therapy, adverse effects and health outcomes.
DRUG USE EVALUATION
Drug use evaluation, sometimes referred to as drug utilization review, is a system of continuous,
systematic, criteria-based drug evaluation that ensures the appropriate use of drugs.
It is a method of obtaining information to identify problems related to drug use and if properly
developed, it also provides a means of correcting the problem and thereby contributes to
rational drug therapy.
Drug use evaluation can assess the actual process of administration or dispensing of a
medication (including appropriate indications, drug selection, dose, route of administration,
duration of treatment and drug interactions) and also the outcomes of treatment (e.g. cured
disease conditions or decreased levels of a clinical parameter).
DRUG USE EVALUATION
The objectives of drug use evaluation include:
– ensuring that drug therapy meets current standards of care
– controlling drug cost;
– preventing problems related to medication;
– evaluating the effectiveness of drug therapy; and
– identification of areas of practice that require further education of practitioners.
DRUG USE EVALUATION
The main source of data for drug use evaluation is the patient records.
An identifiable authoritative group, such as the drugs and therapeutic committee, usually carries
out reviews of drug use in a hospital or health facility.
This group has the responsibility for drawing up the guidelines, criteria, indicators and
thresholds for the evaluation.
Drug use evaluation may be based on data collected prospectively (as the drug is being
dispensed or administered) or retrospectively (based on chart reviews or other data sources).
DRUG USE EVALUATION
Typical criteria reviewed in prospective studies include the In retrospective studies, the criteria reviewed include:
following
– evaluation of indications;
– indications;
– monitoring use of high-cost medicines;
– drug selection;
– comparison of prescribing between physicians;
– doses prescribed;
– cost to patient;
– dosage form and route of administration;
– adverse drug reactions; and
– duration of therapy;
– drug interactions.
– costs;
– therapeutic duplication;
– quantity dispensed;
– contraindications;
– therapeutic outcome
– adverse drug reactions; and
– drug interactions.
DRUG USE EVALUATION
It is possible to incorporate some of the above criteria into databases thus allowing drug experts
to evaluate any items that do not meet established criteria.
For meaningful results to be obtained from drug use evaluation a reasonable number of records
need to be assessed.
A minimum of 50 to 75 records per health care facility is considered adequate.
However, the number of records sampled would depend on the size of the facility and the
number of prescribers.