FACULTY OF PHARMACY

hdAheA University AND

Norbert Wiener BIOCHEMISTRY

Training course:
Pharmacovigilance and technovigilance.

Efficacy and safety of medications.

Q.F. Ernesto Raúl Torres Véliz .

Mg. Experimental pharmacology. UNMSM
Dr. Pharmacy and Biochemistry. UNMSM

Lima - 2019
 FACULTY OF PHARMACY AND
BIOCHEMISTRY
The Rational Use of Medicines (URM) is a process
that includes the appropriate prescription of
Context medicines, the timely availability of effective, safe and quality
medicines, at the best cost-benefit ratio, under conditions of
conservation, storage, dispensing and proper administration .

Chain the
medicine

Rational use of medications: A task for everyone. MINSAL Chile

2010
 FACULTY OF PHARMACY
AND
BIOCHEMISTRY
6. INCORRECT PRACTICES IN THE PRESCRIPTION OF MEDICATIONS
• Use of medications in clinical situations that do not require it.
• Omit non-pharmacological measures when relevant.
• Use of pharmaceutical products of questionable efficacy and/or safety or their unjustified association.
• Poor choice of medication or medications for the problem diagnosed in the patient.
•Over-prescription "polypharmacy" or under-prescription of medications.
• Failure in dosage, choice of route of administration and/or duration of treatment.
•Omission of relevant patient characteristics or cultural barriers, for therapy adjustment.
• Insufficient or no explanation to the patient of the aspects of the prescription.
• Prescription of expensive medications with cheaper alternatives that are equally effective and safe.
• Belief that generic medications are of inferior quality than their brand-name equivalents.
•Tendency to use new medications without an adequate comparative evaluation of their benefit and cost.
•Poor monitoring of pharmacotherapy that can prevent early detection of therapeutic failure and/or adverse drug reactions.
• Write the prescription and instructions for the patient in illegible handwriting.
•Indications given to the patient that are not well recorded, as well as not clearly and precisely detailing the
pharmacological and non-pharmacological measures.
Manual of Good Prescription Practices / Ministry of Health. General Directorate of Medicines,
Supplies and Drugs. — Lima: Ministry of Health, 2005. 94 p.; illus.
 FACULTY OF PHARMACY
Norbert Wiener
University AND BIOCHEMIS
TRY
■ History
■ Physical Resolution of health problems
examination
■ Rational use Therapeutic Objectives
of technology Therapeutic Strategies
■ Diagnosis Doctor-patient
■ Pathophysiology
Relationship
Analysis
Non-pharmacological
Analysis and
clinical and treatment Pharmacological
decision therapeutic treatment Combination of
making decision both
making
Tarmac Selection
Patient's Health
Efficiency, Safety
health problem Effectiveness, Cost
problem under Convenience
control

Results
monit Patient
or health 4
(SFT) equipment
 FACULTY OF PHARMACY
hdAheA University AND
Norbert Wiener BIOCHEMISTRY

What is called effectiveness of medications?

Ability to prevent or mitigate the natural course of the disease. If it is capable
of meeting the therapeutic objectives set.
Ability of a medication to produce the proposed effects determined by
scientific methods.
Efficacy is the degree to which a given intervention produces a beneficial
outcome under certain conditions.

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 FACULTY OF PHARMACY
hdAheA University AND
Norbert Wiener BIOCHEMISTRY

How is the effectiveness of a medication proven?

Through a controlled, randomized and double-blind clinical trial (ECCA). Called
“gold standard for the evaluation of medicines”.

• Controlled: This refers to the fact that it is an “experimental” study, that is, there
must be a control group (takes a placebo) and a treated group (takes a test drug.

• Randomized: It refers to the fact that the patients selected with the diseases to be
treated are randomly assigned to the control group and the treated group. There
should be no subjective influences in the assignment

• Double blind: This means that neither the patients nor the doctors know who is
taking the trial medication. This avoids the influence (greater care) of doctors with
patients in the treated group.
 FACULTY
iheAndA University OF
“4P4VP Norbert Wiener PHARMACY AND
BIOCHEMISTRY
What is evaluated in a drug efficacy trial?

A soft variable therapeutic objective. It refers to a goal that can be

achieved in a short time (weeks or months) and in a short number of patients
(hundreds).
Examples:
• Control blood pressure to < 140/90 mm Hg, within one month of treatment.
• Decrease glycosylated hemoglobin in three months of treatment.
• Reduce mild to moderate pain.

When is the efficacy trial of a medication carried out?

Before being marketed, generally in phase III clinical study. The ECCR is essential for
the registration of a new medicine.
Mg. Ernesto Torres Veliz 7
 FACULTY OF PHARMACY
Norbert Wiener
University AND
BIOCHEMISTRY

Algorithm for classifying types of clinical research

Types of Studies-Hierarchy of Evidence
Does the researcher assign the exposure?

YE NO
AH
Quality of
Experimental study Observational study evidence

random assignment Comparison of groups?

eta-analysis
Y
IF E
ÉCCwithP Study Reviews
assignment CCTnon- AnalyticalA study
H descriptive RCT Systematics
. random. random Group
against
Temporal Notification of a Clinical Trials
address case Notification of a
series of cases Randomized
Exposition- outcome
Exposure ending at the same
Cohort Studies
studio
time
Case-Control Studies
Study of cases
Study
Case Series Case
transvers
cohorts and
controls
e Report Expert
Exposition-,— Magnitud
denouement Opinion
e of Bias
 FACULTY OF PHARMACY
University
Norbert Wiener
AND
BIOCHEMISTRY
Under what conditions is the efficacy trial of a medication carried out?

It is carried out under ideal conditions, that is, conditions are sought in which
variables that could influence the results are ruled out.
For example, all patients in the study (control and treated group) receive the same
diet, physical activity, have a range of age (eg, 60-70 years), gender (eg, only
men), are constantly supervised, etc. In other words, the aim is to ensure that the
result only depends on the use or not of the medication.

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 FACULTY OF PHARMACY
hdAheA University AND
Norbert Wiener BIOCHEMISTRY

How is the result of the effectiveness study evaluated?

• It is statistically analyzed whether the difference found (eg, patients who controlled
BP below 140/90 mm Hg) in both the control and treated groups is significant.
• Analyze the placebo effect : Patients who improved without treatment
(psychological effect).
• Analyze the nocebo effect : Patients from the control group who manifest ADR.
• Analyze patients who did not respond to treatment in the treated group (influence of
pharmacogenetic variables (at pharmacodynamic or pharmacokinetic level)
 FACULTY OF PHARMACY AND
University BIOCHEMISTRY
Norbert Wiener

What is called effectiveness of medications?

Ability to prevent or mitigate the natural course of the disease. If it is capable of
meeting the therapeutic objectives set in real conditions , during its marketing

They are observational studies, there is no supervision.

It is evaluated whether, under real conditions, the

medication used is capable of achieving hard variable
objectives, for example, decreased mortality, decreased
complications.

99870
Mg. Ernesto Torres Veliz
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 FACULTY OF PHARMACY AND
BIOCHEMISTRY

Table 2.2. Differences between the use of medications in the phase III clinical trial and the
usual clinical practice

Efficacy clinical trial (phase III) Clinical practice effectiveness (phase

IV)

Characteristics

Number of patients 102 -103 104- 107

Problem studied Well defined Not well defined by fact-
associated res

Population Homogeneous Heterogeneous

Other treatments They are avoided Often present
Dose Fixed Variables
How to use Keep going Often intermittent

Patient monitoring Rigorous less rigorous

Duration Days-weeks Days-years
Source: Modified from Laporte L and Tognoni G. Principles of epidemiology of the drug. 1993:7.

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 FACULTY OF PHARMACY AND
BIOCHEMISTRY

Example of application of definitions:

Losartan (antihypertensive of choice)
P Pharmacotherapeutic effectiveness (meets hard variable therapeutic objectives) In addition to
controlling BP, it reduces mortality and complications
> Therapeutic efficacy (Meets soft variable therapeutic objectives) Controls BP below 140/90
mm Hg (antihypertensive.)
> Pharmacological effect : Hypotensive.
> Action : vasodilator (relaxes vascular smooth muscle)
> Mechanism of action :
It antagonizes the angiotensin II receptor, preventing the activation of its receptor and
decreasing the formation of the second messenger Inositol triphosphate (IP3), as a
consequence it decreases the release of calcium from the sarcoplasmic reticulum…finally
the light chain myosin kinase is not activated .

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 FACULTY OF PHARMACY
hdAheA University AND
Norbert Wiener BIOCHEMISTRY
How do we evaluate the safety of medications?
It begins to be evaluated from its preclinical research (experimental
animals. (acute, chronic toxicity, teratogenicity, mutagenicity,
carcinogenicity, etc.).
There must be documented evidence of unwanted and toxic effects
that occur during clinical trials and preferably during the marketing
stage (phase IV).
A medication is considered relatively safe if, during 10 years of
pharmacovigilance, it has not demonstrated adverse effects that
endanger the patient's life.

How is RAM classified?

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 FACULTY OF PHARMACY
hdAheA University AND
Norbert Wiener BIOCHEMISTRY
CIOMS Classification ( Council for International Organizations of Medical
Sciences)
• Very common : They occur with a frequency greater than or equal to 1 case in every
10 patients who come into contact with the medication. It is expressed ≥ 1/10)
• Frequent : They occur with a frequency greater than or equal to 1/100 but less than
1/10. It is expressed (1/100 and < 1/10)
• Infrequent: They occur with a frequency greater than or equal to 1/1,000 but less than
1/100. It is expressed (≥ 1/1,000 and < 1/100)
• Rare : They occur with a frequency greater than or equal to 1/10,000 but less than
1/1,000. It is expressed (≥ 1/10,000 and < 1/1,000)
• Very rare: They occur with a frequency of less than 1/10,000. It is expressed <
1/10,000

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 FACULTY OF PHARMACY AND
BIOCHEMISTRY
Cardiac disorders:
Common: bradycardia.
Rare: deterioration of heart failure, precipitation of heart block.

Vascular disorders:
Application example: What adverse Common: cold extremities.
Rare: hypotension (orthostatic) which may be associated with syncope, exacerbation of intermittent claudication if

effects can I warn the patient about already present; in patients sensitive to Raynaud's phenomenon.

during dispensing? all? AEMPS atenolol Respiratory, thoracic and mediastinal disorders:
Rare: Bronchospasms in patients with bronchial asthma or a history of asthmatic disease.

technical sheet Gastrointestinal disorders:

Common: Gastrointestinal disorders, nausea, vomiting, diarrhea, and constipation.
4.8, Adverse reactions Rare: dry mouth.

The following terminology has been used to classify the occurrence of adverse reactions: very common
(21/10); common (1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (> 1/10,000 to <1/1,000); very rare Hepato-biliary disorders:
(<1/10,000), not known (cannot be estimated from available data). Uncommon: elevated transaminase levels.
Rare: liver toxicity including intrahepatic cholestasis.
Blood and lymphatic system disorders:
Rare: thrombocytopenia. Skin and subcutaneous tissue disorders:
Rare: purpura, rash, alopecia, psoriasis- like skin reactions, worsening of psoriasis.
Psychiatric disorders: Not known frequency: hypersensitivity reactions, including angioedema and urticaria.
Uncommon: sleep disorders.
Rare: depression, nightmares, anxiety, confusion, psychosis and hallucinations.
Reproductive system and breast disorders:
Rare: Impotence.
Nervous system disorders:
Rare: dizziness, headache, paresthesia. General disorders and condition of the site of administration:
Common: fatigue, sweating.
Eye disorders:
Rare: dry eyes, visual disturbances. Complementary explorations
Very rare: increased ANA (antinuclear antibodies). 16
Cardiac disorders:
Common: bradycardia.
Rare: deterioration of heart failure, precipitation of heart block.
 Stage I
20 - 50 healthy volunteers for
gather preliminary data
FACULTY OF PHARMACY
AND
BIOCHEMISTRY
Experience shows that a large number of Figure 1 Clinical development of drugs
effects adverse,
Interactions (with foods or other drugs) Stage III

and risk factors do not come to light until 250 - 4000 patients in more groups
heterogeneous, to determine the
years after a drug is marketed short-term safety and efficacy

Experimentation on animals for Stage II

study of acute toxicity, 150-350 patients,
organic lesions, dependency to define the
dose, metabolism, recommendations
Only drugs should be selected for which kinetics, carcinogenicity and about security
and posology
Stage IV
Post-approval studies on
mutagenicity/teratogenicity
there is sufficient scientific information from certain safety issues

controlled clinical trials, epidemiological

studies or both, and for which there is Predictive
experimentation Stage I Stage II Stage III
Stage IV Spontaneous Post-
Approval Notification
evidence of effectiveness in their use in with animals

different contexts. Yo
Record
The drugs of recent < Post-approval >

marketing should only be included if they Development

have advantages that distinguish them

from those currently used

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 FACULTY OF PHARMACY
University
Norbert Wiener
AND
BIOCHEMISTRY
 LIFESTYLE CHANGES
Appropriate lifestyles
(related to physical
activity, diet, salt
consumption, ethanol,
stress) help medications
achieve their
effectiveness and safety.

Mg. Ernesto Torres 18

Veliz

ii

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 FACULTY OF
iheAndAUniversity
University FACULTY OF PHARMACY
PHARMACY AND
“4P4VP Norbert Wiener AND BIOCHEMISTRY
Norbert Wiener
BIOCHEMISTRY

Thank you for

your
attention.

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