Measurement of Outcomes in Pharmacoepidemiology

Definition of Outcome - In treatments and health care programs, outcome is the result of treatment or patient
care which include both positive and negative results.

Definition of Outcome Measurement – outcome measurement is defined as the systematic quantitative analysis
of the outcome indicators at a point of time inorder to find out whether the goals of patients were identified and
achieved.

Outcomes measures are based on:

1. Clinical Results – Improvement in the condition, Deterioration/worsening of condition or no change in

the condition
2. Functional Results – factors like ability to work, level of functioning (impairment, activity limitation
and participation restriction), whether supervision needed or not
3. Symptom based -days free of pain / an event
4. Patient satisfaction - various aspects of care (delivery of care, effects on daily activities or life
satisfaction)
5. Economic Measure – here the factors like cost of financial burden and the benefits obtained are noted
6. Humanistic Measures – Various aspects of quality of life (QOL) are included here

Outcome of Disease
1. Death – A bad outcome
2. Disease – a set of symptoms, Physical signs and Laboratory abnormalities
3. Discomfort –symptoms such as pain, nausea, itching etc
4. Disability – impaired ability to go for usual activities at home, work or recreation
5. Dissatisfaction – emotional reaction to disease such as sadness or anger

Classification of Outcome
The therapeutic outcomes may be classified as cure, improvement, no change or deterioration. On the other
hand they can also be classified as success or failure.
o Morbidity and mortality are the most commonly used measures of outcome. Morbidity is measured as
the number of cases of disease or events that occur per unit population (per 100), unit of time (per year)
or both (events/100/year)
o Other measures of morbidity are, the number of hospitalizations resulting from drug use or prevented by
drug use or days of hospitalization and deaths due to drugs or prevented by the use of drugs
The measurement of outcomes in Pharmacoepidemiology can be done by two approaches:

1. Outcome measures
2. Drug use measures

1) Outcome measures

The occurrence of pharmacoepidemiological outcomes is commonly expressed by statistical

measurements such as

a. Prevalence
b. Incidence
c. Cumulative incidence and
d. Incidence rate

a) Prevalence
• Prevalence in Pharmacoepidemiology is the proportion of people affected with a disease or exposed to a
particular drug in a population at a given time
• It is usually obtained from cross sectional studies like surveys and occasionally based on registers of
people affected with disease or exposed to drug
• Prevalence varies between 0-1, it can also be expressed as a percentage (cases per 1000 exposures)
• The prevalence at any given time is called point prevalence and for a year is called annual prevalence
• Mathematically,
That is Prevalence = a/b
a- number of populations with disease at a given time
b- Total number of population at a given time
Eg - If there are 1000 patients with epilepsy in a district of 10, 00000 populations, the prevalence
of epilepsy in that district will be 1000/10, 00000 or .001%

Eg- among 7.8 lac population of a city, 1.2 lac suffered from chikungunya. The prevalence of
Chikungunya in that city (P) = 0.15 %

b) Incidence:
• It is the measure or frequency with which a new disease occurs or the rate at which people free from
disease develop the disease, during a specified period of observation. Generally a period of one year is
used for the measurement of incidence
 • The important aspects of incidence are :
o The need to define the population of interest which is often known as inception cohort
o All persons in the inception cohort should be free from disease
o A period of observation should be specified
o All the persons should be followed for the specified time

Relationship between prevalence and incidence

P=IxD
Where I =Incidence
D=duration of disease
• In case of descriptive studies two measures of incidence are commonly used :
Cumulative incidence (CI) and incidence density or incidence rate (IR)

c) Cumulative incidence (CI) (incidence proportion):

• It is the number of new cases divided by the size of the population

• It estimates the probability or risk that a person can develop the disease over the specified period.
Ex. if there are 100 new cases of epilepsy in a district of 10, 00000 population, the CI of epilepsy
in that district will be 100/10, 00000 or 1/10000

d) Incidence rate (IR)

• It is the number of new cases per unit of person-time (person-days, person-months or person years) at
risk.
• Generally it is expressed as cases/person-year exposures
Eg – In a study of ADR of Ampicillin 100 patients were followed for six months and 100
patients were followed for one year. A total of 40 persons developed GI discomfort. The total
observations are 1800 person-months or 150 person-years. Here the incidence density or incidence rate
is 40/150 person-years of exposure to Ampicillin.

What is person-time?

• It is an estimate of the actual time-at-risk in years, months or days that all persons contributed to study.
• In certain studies people are followed for different length of time as some will remain disease-free
longer than others.
 • A subject is eligible to contribute person-time to the study only as long as that person remains disease-
free and therefore, still at risk of developing the disease
• By knowing the number of new cases of disease and the person-time-at-risk contributed to the study, an
investigator can calculate incidence rate.
• IR= the number of new cases of disease during a period of time/the person-time-at-risk.
• The denominator for IR (person-time) is a more exact expression of the population at risk during the
period of time when the change from non-disease to disease is being measured.
• The denominator for IR changes, as persons originally at risk develop disease during the observation
period and are removed from the denominator

Calculating person-time:

❖ An investigator is conducting a study of the incidence of second MI. He follows 5 subjects from baseline
(after first MI) for up to 10 weeks.
Solun:
As we know, person-time is the sum of total time contributed by all subjects (days each subject
remained as non-case from baseline)
Subject A: 53 days Subject B: 70 days
Subject C: 24 days Subject D: 70 days
Subject E: 19 day
o Total person-days = 236 person-days
o Now, 236 p-d becomes denominator in measuring IR
o The total no. Of subjects becoming cases (A,C,E) is the numerator
o Therefore,
The IR of sec.MI is 3/ 236 p-d = 0.0127 cases per person-day. (1.27 cases/ 100 person-
days or 12.7 cases/1000 person-days
• Person-days, can be converted into any interval appropria5771te to the disease being studied.
o Sec.MI may be expressed in cases per person-year by:
0.0127cases/person-day) X 365 = 4.6 cases/person-year

2) Drug use measures

1. Monetary units
2. Numbers of prescription
3. Units of drug dispensed
4. Defined daily doses
 5. Prescribed daily doses
6. Medication adherence measurement

1. Monetary units
• Drug use has been measured in monetary units to quantify the amounts being consumed by
population
• Monetary units for drug use measures are done by pharmacoeconomic studies. They are cost-
effective analysis, cost-benefit analysis, cost minimization analysis and cost utility analysis
Advantage
• It can indicate the burden on individual, family, society, organizations or government from drug use.
Disadvantage
• A drug may have different dosage forms and strengths in the market and the price may vary

2. Number of prescriptions.
• It has been used in research or statistical method due to the availability and ease
Advantages
• It is used to get rough estimates like percentage of analgesic drugs, oral contraceptives, antibiotics
used by the population
• It helps to give an estimate of number of people exposed to certain drugs or number of episodes of
treatment programmers in our health care
• It also help to find whether there is increase in the number of prescription during certain periods
Disadvantages
• There may be variations with respect to dose, dosage form and duration of use in individual
prescriptions.
• The quantities dispensed from pharmacies vary with the prescribed quantities for various reasons.

3. Units of drug dispensed

• Units of drug dispensed like number of tablets or capsules or doses of vaccines is easy to obtain and
is used in this method
Advantage
• When compared to number of prescriptions it is easy to find the number of drug dispensed
• It helps to analyze the drug use trends in various countries or various states or territories of a country
Disadvantage
 • No information is available on the quantities actually taken by the patient. People may not use
certain dispensed drugs for various reasons. Hence it is difficult to determine the actual number of
patients exposed to the drug

4. Defined daily doses (DDDs)

• According to WHO, “DDD” is a statistical measure of drug consumption
• DDD is defined by WHO as “It is the assumed average maintenance dose per day for a drug used for
its major indication in adults”. It is not to be confused with the therapeutic dose or dose actually
prescribed by the physician for an individual patient.
• For example paracetamol used as an analgesic (pain is the main indication). It is having a DDD of 3g
means, that a patient uses paracetamol as a pain killer (main indication) uses 3g in a day or within a
period of 24 hours.
• If DDD is known for a drug, the Drug usage (DDDs) can be calculated as follows:
Drug usage (DDDs) = Item issued x amount of drug per item/DDD
For example if a patient consumes 24 paracetamol 500mg tablet having DDD 3g over a certain span
of time
The Drug Usage (DDDs) = 24 x 500/3000 = 4mg
• Example 2
Treatment with two products each contains one active ingredient:
Product A - tablet containing 20mg of Substance X (DDD=20mg)
Product B – tablet containing 25mg of substance Y (DDD = 25mg)
The dosing schedule for one tablet A+ one tablet B daily will be calculated as consumption of 2
DDDs
• Doses for individual patients and patient groups will often differ from DDD and will necessary have
to be based on individual characteristics (eg-age and weight) and pharmacokinetic considerations.
• It is normally expressed as DDD/1000 patients or inhabitants/day or DDD/patients or
inhabitants per year or DDD/100 bed day
o DDD/1000 inhabitants per day
⮚ This measure is generally employed for medication used in the treatment of chronic
conditions.
⮚ As a result of 10 DDD per 1000 inhabitants per year is interpreted as follows:
10 DDDs of the drug are utilized in a representative group of 1000 inhabitants on any given
day of the year studies
 o DDD/inhabitants per year
⮚ This measure is normally employed for drugs used in acute treatment
⮚ A result of 10 DDD per inhabitant per year is interpreted as follows:
An average of 10 days of treatment with a specific medication per inhabitants per year
o DDD/100 bed days
⮚ This measure is applied in analyses of hospital drug use
⮚ A result of 10DDD per 100 bed days can be interpreted as follows
10% of the in patients receiving the medication daily
Use
• It is used to standardize the comparison of drug usage between different drugs or between different
health care environments.
• It helps the researcher to assess trends in drug consumption and to perform comparison between
population group
• It is helpful in describing and comparing patterns of DU and provides data for estimation of ADR
rates
Advantage
• The DDD provide a fixed unit of measurement independent of price and dosage form
• Its usefulness for working with readily available drug statistics
• It allows comparisons between drugs in the same therapeutic class
Disadvantage
• Drug consumption data presented in DDDs only give a rough estimate of consumption and not
exact picture of actual dose
• Pediatric doses are often not considered in this calculation
• DDDs are not established for topical products, sera, vaccines, general and local anesthetics
• It is difficult to estimate when doses vary widely like with antibiotics or if the drug has more than
one major indication
Ex: aspirin low doses are used in cardiology while high doses are used for inflammatory
conditions

Prescribed daily doses (PDD)

• It is the average daily dose of a drug that has actually been prescribed
• It is calculated from sample of prescriptions or medical and pharmacy records
• In case of drugs where the recommended dosage differs from one indication to another it is
important to link the diagnosis to PDD (Eg-Psychiatric dosing)
Disadvantage
• It does not reflect actual drug utilization. Because some prescribed medications are not dispensed
and the patient does not always take all the medications that are dispensed

Medication adherence measurements

Adherence to medication is a crucial part of patient care and for reaching clinical goals. According to WHO
“increasing the effectiveness of adherence interventions may have a far greater impact on the health of the
population than any improvement in specific medical treatment”

Nonadherence leads to poor clinical outcomes, increase in morbidity and death rates, and unnecessary
healthcare expenditure. Approximately 50%–60% of patients are nonadherent to the medicine that they have
been prescribed, especially those suffering from chronic diseases. As a result, more than 30% of medicine-
related hospital admissions occur due to medication nonadherence

The WHO defines adherence as “the extent to which the persons’ behaviour (including medication-taking)
corresponds with agreed recommendations from a healthcare provider”.

According to WHO, there are multiple factors leading to poor medication adherence, normally classified into
five categories: socioeconomic factors, therapy-related factors, patients-related factors, condition-related
factors, and health system/health care team- (HCT-) related factors 

Medication adherence measurements include direct and indirect measurements.

1) Direct measures or sample collection method –

This includes measurement of the drug or its metabolite concentration in body fluids, such as blood or urine and
evaluation of the presence of a biological marker given with the drug

Even though direct measures are considered to be the most accurate and can be used as a physical evidence to
prove that the patient has taken the medication, but there are many drawbacks regarding their usage. Direct
measures are very expensive and difficult to perform as many technicians and professionals are required to
monitor the process and carry out the tests.  Traces of neuroleptic and psychiatric medications can be detected
in the blood even long after stopping the medication.  For instance riboflavin, a biological marker, is simply
nonquantitative for detection. Additionally, drug-drug interactions and drug-food interactions can hinder the
accuracy of this method
2) Pill counts

This indirect measure counts the number of dosage units that have been taken between two scheduled
appointments or clinic visits.

The low cost and simplicity of this method contribute to its popularity.

However, several limitations have been identified. Removing the correct number of dosage units from the
container does not necessarily mean the patient follows the dosing regimen consistently.

3) Electronic Medication Packing (EMP) Devices

EMP devices are “adherence-monitoring devices incorporated into the packaging of a prescription medication.”
The Medication Events Monitoring System (MEMS) is the most commonly used EMP device in medication
adherence studies.

The Medication Events Monitoring System (MEMS)

The basic principle of this system is that whenever the medication is removed from the container, a
microprocessor embedded would record the time and date, assuming that the patient has taken that specific dose
at that particular time.

This measure is being highly accurate in several studies. It helps identify whether the nonadherence is sporadic
or consistent or any other abnormal medication-taking pattern

4) Clinical assessment and self report

These methods are the least reliable among all. But also, their low cost, simplicity, and real-time feedback have
contributed to the popularity of this method in clinical practice.

Purposefully or accidently or faulty communication skills and questions constructed by the interviewers as well
as the design of survey can occur false data input.  Blaming the patients for not fulfilling their prescribed
regimen and patient’s psychological state are the leading drawbacks of these approaches

a) Patient kept diaries

This is the only self-report tool that is consistently documented with how the patient follows their prescribed
regimen. However, overestimation is very common and an average of 30% surplus of diary entries has been
shown to occur when comparing with different results from MEMS data 
b) Patient interviews

Interviewing patients by health care professional is generally an easy-to-use, low-cost subjective method to
assess patient’s adherence. Questions can be based on patient’s knowledge on the personal prescribed regimen,
including drug’s name, schedule, and indications. Healthcare professionals then evaluate their response to
determine the level of adherence. But it is stated that there is only limited evidence on the relationship between
the patient’s knowledge on their medication regimen and actual adherence 

c) Questionnaires and scales

Self-report questionnaires should be completed by patient themselves or their caretakers. However,

questionnaires can be difficult for patients with low literacy levels

i) Brief medication questionnaire - (The Brief Medication Questionnaire is not abbreviated as BMQ, since BMQ
usually stands for Belief about Medicines Questionnaire.)

⋅ It consists of three different screens, a 5-item Regimen screen, a 2-item Belief screen, and a 2-

item Recall screen. These screens assess how patients took each of their medications in the past week,
on drug efficacy and bothersome features and remembering difficulties, respectively.

ii) Hill-Bone Compliance Scale

⋅ It targets patients with antihypertensive medication only.

⋅ The test consists of 3 subscales, medication-taking behaviour, ability to keep appointment, and sodium
intake and is rated on a four-point Likert-type scale.

iii) Medication Adherence Questionnaire (MAQ)

⋅ The MAQ is also known as the 4-item Morisky Medication Adherence Scale (MMAS-4). The closed
question format with “yes-saying” allows disclosures of nonadherence 

iv) Eight-Item Morisky Medication Adherence Scale (MMAS-8)

⋅ Based on medication adherence questionnaire (MAQ) morisky et al developed 8 item medication

⋅ In this adherence scales the first seven items are Yes/No responses while the last item is a 5-point Likert
response. It focuses on medication-taking behaviours especially related to underuse, such as
forgetfulness. So barriers to adherence can be identified more clearly

v) The Self-Efficacy for Appropriate Medication Use Scale (SEAMS)

 ⋅ The SEAMS is a 13-item, 3-point Likert-type scale focusing on self-efficacy in chronic disease
management while measuring barriers to medication adherence.

vi) Medication Adherence Report Scale (MARS)

⋅ It consists of 10 questions with a simple scoring to evaluate patient’s adherence behaviour during the
past week 

5) Secondary database analysis

a) Medication Possession Ratio (MPR) Day’s supply obtained/refill interval or fixed interval

b) Continuous, Multiple Interval Measure Cumulative days’ supply obtained over a series of intervals/total
of Medication Acquisition (CMA) days from the beginning to the end of the time period

c) Continuous, Multiple Interval Measure Cumulative days without any medication over a series of
of Medication Gaps (CMG) intervals/total days from the beginning to the end of the time period

d) Continuous, Single Interval Measure of

Day’s supply obtained in each interval/total days in the interval
Medication Acquisition (CSA)

e) Continuous, Single Interval Measure of

Number of days without any medication/total days in the interval
Medication Gaps (CSG)