Διάλεξη στα πλαίσια του 4ου Συμποσίου Φαρμακοεπιδημιολογίας

1. Η συνεισφορά της
Γενικής / Οικογενειακής Ιατρικής
στη
Φαρμακοεπιδημιολογία
Ευάγγελος Α. Φραγκούλης, MD, MSc
Γενικός / Οικογενειακός Ιατρός
Αν. Αρχίατρος ΕΔΟΕΑΠ

2. Φαρμακοεπιδημιολογία
Φαρμακολογία
Επιδημιολογία
Κλινική πρακτική
Pharmacoepidemiology - the study of the use and effects/side-effects of drugs in large numbers of
people with the purpose of supporting rational and cost-effective drug use in the population thereby
improving health outcomes

3. Pharmacoepidemiology
Data
Health Medications
People

4. Νeed to generate data on the safety of a medicine
after it had been marketed
• during the clinical development of a drug, efficacy and safety evaluated
under tightly controlled conditions in a relatively small number of people.
• large amount of information about the safety of a drug emerges only in the
post-marketing phase, as more and more individuals are exposed to the
drug / patients having co-morbid conditions and those being treated with
concomitant medical products that receive the medicine
• post-marketing PE studies generate crucial data for an ongoing risk
assessment and characterization of a product’s risk profile
• informed decisions on risk minimization can be made

5. Need to study a drug’s use in the “real world”
• It is important that all stakeholders understand how drugs are used in
the general population
• there is a need for continuous surveillance of drug use and ways to
evaluate how patient characteristics influence drug utilization and
clinical outcomes, both the expected and unexpected clinical outcomes

6. Examples of questions that can be answered using
pharmacoepidemiology
• Patterns of use
• What are the patterns of drug utilization?
• How are drugs used in clinical practice?
• How are drugs used in specific patient populations, such as women, children, the elderly, or racially diverse patients?
• How long do people take this drug?
• Do certain patient groups stop taking the drug?
• What are the medication adherence and persistence rates?
• Safety
• What is the frequency of drug-induced outcomes?
• Are there rare adverse events that occur with this drug product, and if so, how often do they occur? Is this a causal
relationship?
• Are there drug–drug interactions with this drug product that have not been identified previously? How frequently do drug–
drug interactions occur in the population?
• Do certain risk factors predispose patients to adverse drug reactions?
• Are there drug–disease interactions associated with this drug?
• Effectiveness
• What are the clinical benefits of this drug? Is the drug effective when used in the “real world”?
• Is drug A more effective than drug B?
• Is a drug product effective for an off-label use?
• What is the effect of using the drug over time?
• Economic evaluations
• What are the economic consequences of therapy?

7. Role of Primary Care Physicians in
Pharmacoepidemiology
• in a prime position to help identify and report issues and adverse drug events, which can then be
studied using pharmacoepidemiology techniques
• lessons learned from individual patient encounters can be used to develop research questions
• routinely collected data from electronic health records (including primary care
databases, registries, and administrative healthcare claims) are a resource for research
• provide guidance on the development of reporting forms and databases, which can provide data
for pharmacoepidemiology studies
• users of pharmacoepidemiology research findings. They can apply study findings at the individual
patient level or at the population level. With evidence-based medicine increasingly being
emphasized, practitioners should consider evidence when making drug therapy choices for an
individual patient
• interested in what occurs in the “field” (the “real world”) e.g., in medication adherence- monitor
medication adherence rates and the outcomes associated with adherence in a large population
• use the findings from pharmacoepidemiology studies to develop population-based interventions

8. Case reports/series
• While a case report is an event seen in a single patient,
a case series describes all the patients who had the same
exposure and had a similar outcome
• Although it is data only from one or a few patients, and cannot
provide a causal association between exposure and the event
with any degree of certainty,
often such case reports/series can help generate a hypothesis
which can then be put to test with rigorous designs in a larger
population

9. Hypothesis generation- strengthening- testing
• case reports/case series generate hypotheses - in
pharmacovigilance programmes these come
through spontaneous reporting systems
• Ideally to test these hypotheses cohort or case-
controlled studies need to be conducted. When
the incidence of an adverse effect is ≥ 3/10,000
cohort or case control studies must include
≥10,000 individuals to be 95% certain of observing
≥1 case of any adverse effect.
• A study of this size is expensive, difficult to
perform and may take too long for addressing
serious regulatory, commercial, and/or public
health crises.
• Of late therefore computerized databases
containing medical care data, the “automated
databases,” have become popular as potential
data sources for pharmacoepidemiology studies
Case- reports
Case-studies
Case-control studies
Cohort-studies
RCTs

10. Routinely collected health data
• a broadly accepted, necessary, and cost effective
resource widely used for evaluating the real world
effectiveness and safety of medicines.
• Studies conducted with routinely collected data are
necessary
• Clinical trials might not be available, or ethical, and could have
limitations owing to restrictive inclusion and exclusion criteria.
• Primary data collection could be costly or infeasible, have limited
statistical power to detect safety events, or have durations that prevent
the assessment of long term safety outcomes.
• can be used to provide timely answers and reduce waste in biomedical
research when analysing important and novel healthcare issues
BMJ 2018;363:k3532

11. Routinely collected health data
• by-product of the daily operations of healthcare
systems, collected independently of specific a
priori research questions
• broad range of sources (eg, disease registries,
health administrative data, quality/safety
surveillance databases, electronic health records,
and pharmacy data) contain routinely collected
data and have both drug exposure and clinical
outcomes that are of potential use in
pharmacoepidemiology
BMJ 2018;363:k3532

12. Required elements of a database
• Quality: validity, completeness
• Identifier
• Exposure: outpatient drug prescription/dispensing
• Disease: hospitalization diagnoses
• Patient: demographics
• Longitudinal data collection
• Appropriate size
• Hardware systems & data entry / storage / retrieval
• Linkage methodology & software
• Patient data protection & confidentiality

13. Strengths
• Contains information on large populations
• Routine data collection
• Allows for flexibility in design
• No requirement for direct patient recruitment
• Systematic exposure & outcome assessment
• Provides a natural sampling frame
• Reduces study time
• Reduces human resources need
• Reduces cost
• Data collection occurs independently of study initiation

14. Strengths
• accrue patient level health information over a vast period; which is not
possible to assimilate through clinical trials that generally acquire
specific information for a few thousand patients typically over 12–18
months
• Health databases provide an opportunity to examine populations that
are often excluded from randomized controlled trials (RCTs), mainly
the elderly, children, and women

15. These include the need to select elderly or
otherwise high-risk patients in order to
maximize the number of events collected
and thus the power of trials, which means
that uncomplicated, younger and lower
risk patients are rarely represented, with
the unfortunate consequence that little
direct information is available on treatment
benefits in a large sector of the
hypertensive population…..
Perhaps the most important limitation is
the necessarily short duration of a trial (in
most cases 4 to 5 years) ……

16. Pre-Requisites & Limitations
Pre-requisites
• Require highly skilled and experienced human resources
• Raise new confidentiality and ethical issues
• Validity and completeness of the information in the database always has to be checked
Limitations
• Still do cost money
• Information lacking in many databases:
– Medications: OTC, in-hospital, nursing home, oncology & immunesuppressants
– Some potential confounding factors, e.g. life style
– Hospital databases very scarce

17. An ideal database
• requires that all information can be easily linked through the patient’s
unique identifier, the records are updated on a regular basis, and that
the records are verifiable and reliable; however no single database is
ideal (Strom, 2012)
• should include records from both inpatient and outpatient care,
emergency medical care, results of all laboratory and radiological tests,
all prescribed and over-the-counter medications, as well as alternative
therapies for each patient (Torre and Martins, 2012).

18. Primary Care Electronic Health Records
• An Electronic Health Record (EHR) (Masnoon et al., 2018) is
defined as a longitudinal digital record of patient health
information generated by one or more encounters in a
healthcare setting.
• EHRs facilitate a patient-centric design providing a 360-
degree view of their health and wellness, and support
patient tracking, administration, and scheduling of a range of
care-related activities (Deloitte, 2015).
• The EHR also includes data from patient portals or external
laboratories and can be shared beyond the practice site
(Murray, 2014).

22. CPRD - the world’s best database from primary care
• Clinical Practice Research Datalink is a real-world research service supporting
retrospective and prospective public health and clinical studies. CPRD is jointly
sponsored by the Medicines and Healthcare products Regulatory Agency and
the National Institute for Health Research, as part of the Department of Health
and Social Care.
• Collects anonymised patient data from a network of GP practices across the UK.
Primary care data are linked to a range of other health related data to provide a
longitudinal, representative UK population health dataset. The data encompass
60 million patients, including 16 million currently registered patients.
• for >30 years, research using CPRD data and services has informed clinical
guidance and best practice, resulting in over 2,700 peer-reviewed
publications investigating drug safety, use of medicines, effectiveness of health
policy, health care delivery and disease risk factors.

23. Example of dataset structure
patients consult with practice staff, where clinical, therapy, referral, test and immunisation
information is coded in the medical record

24. Data files supplied by the CPRD
File type What it holds Example of contents
Patient Demographic and registration status of patients Patient identifier, month and year of birth, registration status, death date, transfer
out date
Practice Practice administrative data Practice identifier, geographical region, date practice became 'Up to standard', last
data collection date
Staff Information about the staff members entering data Staff identifier, gender, role
Consultation Administrative information about the consultation Date of clinical event, date of data entry, type of consultation, staff identifier and
duration of consultation
Clinical Clinical data regarding medical history Date of clinical event, date of data entry, the CPRD medical code for the chosen
Read code, additional details identifier*, entity type
Additional Clinical
Details (ACD)
Specific data about a clinical event Type of information held, called an 'entity', specific clinical details relating to that
entity
Referral Details on referrals to secondary care or specialists The CPRD medical code for the chosen Read code, method of referral, referral
specialty, urgency of referral
Immunisation Data associated with immunisations Reason for immunisation, type, stage, status and the compound used
Test Test results Type of test, result, normal range of result, unit of measure
Therapy Information about therapies including medications and appliances The CPRD product code for the medication, British National Formulary code,
quantity of product, dose, pack size, number of days prescribed

26. How data from GP practices supports public health
Preventing whooping cough in new-born babies
CPRD data was vital for checking the safety and effectiveness of the vaccine after the programme was
introduced. As a result of the research, all GPs and maternity services now routinely vaccinate all pregnant
mothers from 20 weeks.

27. How data from GP practices supports public health
Confirming the benefit of the flu vaccine for patients with
type 2 diabetes
• CPRD data has been used to investigate the benefits of the flu
vaccine for preventing admissions to hospital and death due to flu.
• individuals who had received the flu vaccine had fewer incidences of
stroke and heart failure over a seven-year period.
• In contrast, individuals with diabetes who had not been vaccinated
had a higher chance of death than those who had been vaccinated.
This study was crucial to confirm the benefits of flu vaccination and
that the current recommendation for yearly immunisation is
worthwhile and accurate.
Vamos EP, Pape UJ, Curcin V, Harris MJ, Valabhji J, Majeed A, Millett C. Effectiveness of the influenza vaccine
in preventing admission to hospital and death in people with type 2 diabetes. CMAJ. 2016 Oct 4;188(14):E342-
E351.

29. Pharmacoepidemiology of COVID-19
• the potential influence of old and new drug therapies on COVID-19 outcomes
• The vast majority of drugs for common conditions such as hypertension, diabetes,
or heart failure are prescribed in primary care
• 15 million prescriptions of angiotensin-converting enzyme inhibitors were
prescribed by UK primary care practitioners last year alone—this drug is now
hypothesized to be significant to COVID-19 outcomes.

30. Advantages for GP practices
joining CPRD
• Contribute to evidence-based medicine
• Ensure your patient population is represented in research evidence
informing clinical guidance and best practice
• Earn extra income for the practice by taking part in questionnaires and
clinical studies
• Your patients can take part in clinical studies
• Receive regular practice-level prescribing and patient
safety quality improvement (QI) reports including patient case-
finding and national practice benchmarking
• Case reviews from QI reports, questionnaires and research
contribute towards annual appraisals and revalidation

31. Quality improvement (QI) reports for
GPs
• Confidential reports designed to help GPs improve the quality of care,
with a focus on prescribing and patient safety, are available for practices
that contribute to CPRD.
• CPRD and the Royal College of GPs (RCGP) have developed confidential, bespoke drug
prescribing reports for individual practices, available for free for GP practices
contributing to CPRD.
• The reports provide a pseudonymised list of patients at the practice so that GPs can re-
identify and review their care. Reports also show the practice’s prescription rate
benchmarked against other participating GP practices. Each report covers a selection
of safety indicators and enables collection of evidence for annual appraisals
under Domain 2 (Safety and Quality).
• Unlike much of the performance measurement information that a practice receives,
this report is for practice-use only and is not made available in the public domain.

33. Quality improvement (QI) reports for GPs

34. Quality improvement (QI) reports for GPs

35. Benchmarking & case-finding

36. A SMR is a structured, holistic
and personalised review of an
individual
who is at risk of harm or
medicines-related problems
because of their current
medicine regimen

38. Pharmacovigilance
• “the science and activities relating to the detection, assessment,
understanding and prevention of adverse effects or any other
drug-related problem” (WHO)
• RCTs provide a lot of information on safety in selected treated
populations under conditions governed by study protocols.
However, this information is limited.
• Further data from post-marketing studies are needed to inform on
safety in populations intended to be treated under real-life
conditions

39. • ένα μέσο για τη συλλογή
πληροφοριών σχετικά με
τις ανεπιθύμητες ενέργειες των
φαρμάκων (και των εμβολίων).
• Οι Eπαγγελματίες Yγείας (ιατροί,
φαρμακοποιοί, νοσηλευτές) έχουν
την υποχρέωση
και οι Aσθενείς έχουν το δικαίωμα
να συμπληρώνουν την Κίτρινη
Κάρτα κάθε φορά που υποψιάζονται
ότι ένα φάρμακο (ή ένα εμβόλιο)
μπορεί να έχει προκαλέσει μία
ανεπιθύμητη ενέργεια.

40. Modified Prescription Event Monitoring
• concerns the safety, utilisation and/ or efficacy of
one medicine which has been recently approved for
use in primary care.
• At a certain interval (3, 6 or 12 months) after the
first prescription for the medicine is dispensed to a
patient, we will send a case report form to the
prescribing GP asking for information about any
events suffered by the patient since the drug was
prescribed. Crucially we do not ask the GP to link
the events encountered by the patient to the
medicine.
• We collate this data from up to 10,000 patients per
study and conduct analysis to determine whether it
is likely that any adverse events can be attributed to
the drug.
• We submit study reports to the drug manufacturer
and the medicines regulators (MHRA and EMA), as
well as publishing our findings in refereed journals.

42. Improving
physician
prescribing

43. “There are no really SAFE biologically active drugs,
there are only SAFE physicians”
Harold A. Kaminetzky
• All drugs have side effects
• Pharmacopepidemiology will never succeed in preventing them
• It can only detect them, hopefully early and thereby educate health
care providers and public which will lead to better medication