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Summary of all the lectures of pharmacoepidemiology
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PharmacoepidemiologyLecture 1 Eelko Hak
16/03/2020 Introduction
Clinical questions:
1. DIAGNOSTICS: What is wrong with this child? Polio.
2. ETIOLOGY: What is causing this disease? Polio is caused by an enterovirus which is a small
RNA virus they block the motor neurons in the spinal cord you get paralyzed.
3. PROGNOSIS: What is the future of this child? The disease will not improve, hopefully stabilize
or worsen.
4. INTERVENTION/THERAPY: What is the best treatment? For these viruses there is no
treatment, because it is a very difficult virus. Physiotherapy or pain treatment is possible.
5. INTERVENTION/PREVENTION: How could this be prevented? Vaccination went wrong at
first; preparing and inventing a safe vaccine takes time.
6. EFFICIENCY/ECONOMICS: How expensive is it to prevent this? Not expensive (25 cents).
Epidemiology is the science that studies the occurrence of diseases in large populations of people as
a function of determinants. So we are looking at a large number of people (1,000-100,000) and look
what determines the disease the determinants: Is it more common in elderly? In man or in
women? Etc.
Epidemiology is an essential science for the conduct of ‘Evidence Based Medicine’.
Four objects of research:
1. Etiology what is the cause of the disease. What kind of virus is it, etc.
2. Diagnostics how can we make sure that a disease is diagnosed as accurate as possible.
3. Prognostics how is the disease going to evolve. What is the typical course of the disease.
4. Intervention what medication should be used to treat the disease. This is for therapy and
prevention.
ACE inhibitors/antimalarials medicine for corona?
Causal associations look mainly at one determinant analytic studies.
Predictive associations are based on all available determinants in order to make the best
diagnosis/prognosis possible descriptive studies.
Process of drug development:
Drug discovery; how should the vaccine be made characterisation formulation; how to produce
at large quantities pre-marketing clinical trials; registration post-marketing
pharmacoepidemiologic studies economical evaluation.
Pharmaco-epidemiology is the scientific field that studies the contribution of drugs in disease
prevention and therapy in large populations.
1
,Typical research questions once a vaccination is spread out in the population:
- What proportion of the population is using the vaccine? Elderly/children/pregnant women
- Which determinants predict the use of vaccines? Age/disease
- Does the vaccine lead to a reduction in diseased cases/mortality/increase in quality of life?
- What type of and how many side effects are caused by the vaccine?
Chloroform used during surgery but patients died because of a heart infarction.
Thalidomide shortened limbs and heart defects in children when pregnant women used it.
Valproic acid spina bifida when using in case of pregnancy.
Cox-2-inhibitors may lead to myocardial infarctions.
Venlafaxine cardiovascular side effects in case of overdose. An ECG must be made before
providing this drug to make sure that there are not already cardiovascular problems.
ACE-inhibitors heart disease.
Rosiglitazone used for diabetes but may lead to hip and wrist fractures.
Diane-35 birth control pill: medication that led to a lot of deaths.
Valdecoxib and Rofecoxib lead to cardiovascular diseases.
Main reasons for dangerous side effects and withdrawal:
1. Clinical trials are not as big as you think.
2. Real world use of a drug differs trials are done in healthy people whereas the users will be
severely diseased.
3. Time plays a role trials have short duration while for some drugs you should use it for a
long time before a disease pops up.
4. Off-label prescribing may bring up unexpected issues e.g. for children.
Problems caused by a drug can also be a result of the patient. A patient can take higher doses than
the maximum daily dose which can lead to side effects or diseases. The drug in itself is then not
harmful as long as patients apply the rules.
There are also drugs that have positive additional effects. Drugs made for a disease have a positive
effect on something else patients than may receive the drug not for the initial purpose. The
mechanism of action then is not completely known; it is only known that it is beneficial.
Drug X = the outcome of the study question. Patient Y = the study domain/hypothetical patient. Age
and sex are the determinants of the outcome.
Drug X = the determinant. Outcome Y = outcome. Disease Z = the study domain/hypothetical patient.
There are different types of studies in epidemiological studies:
- Experimental studies: studies in which the investigator determines what the participant is
going to get randomised control trials/community intervention trials/field trials.
- Observational studies: the investigator has no influence on whether you get your vaccine
descriptive studies/case-control studies/cohort studies.
2
,General characteristics of Randomised Control Trials (RCT):
- There are narrow indications you want everyone to have the drug registered for a certain
indication.
- Homogeneous population make sure that no side effects happen when they do not need
to. Get rid of people who have risk on developing such effect (smoking/pregnancy)
- Small number trials more than 5000 is very uncommon even for standard medication
trials.
- Randomisation a computer determines for you whether you get the vaccine yes or no.
This is controlled to make sure that there is a drug/placebo that is not working to have the
comparison group.
- Double blinding patients as well as the doctors are blinded to whether you got the real
drug or the placebo.
- Relatively short-term therapy trials are very expensive.
All of these trials lead to Evidence Based Medicine.
Characteristics of observational trials post marketing surveillance (PMS). Here there are huge
numbers of patients, with an unlimited time of therapy. Drug-users in practice smokers and
pregnancy occur in the population that use the drug. With PMS, you can study side effects that were
not yet detects during pre-marketing trials. You can also see the real-world effects, such as what
happens in case of comorbidity or combining with other drugs.
RCTs is a really small part of the total patient population that is present. Whereas if you go to the
drug (post marketing) there is a much wider variation of people that is using it.
What clinical information has to be obtained in PMS research?
- Usage and determinants in practice
- Effects in daily practice (when combining with smoking/alcohol)
- Adverse effects
- Drug interactions
- New applications
- Usage of the drug for other indications
- Applied dosage and duration
- Usage/effect in children/elderly and pregnant woman.
- Effect on hard endpoints (disease/mortality)
- Effect on population level (for example corona: might not be very harmful to children but by
vaccinating them, the transmission of the virus may be hindered or even stopped to prevent
spreading to risk groups).
- Costs
- Compliance
- Cost-effectiveness of interventions
Terminology ‘effect’:
- Efficacy: laboratory situations. There is a homogeneous population and a 100% adherence to
protocols. The drug is taken as it should be. The situation is as optimal as possible.
- Effectiveness: the effects of the drugs in the real world. It may be used by people with a
different indication or some who have other diseases that will change the effect of the drug.
- Efficiency: costs in relations to the effects.
PMS is phase IV research where you monitor all desirable and undesirable effects of drugs to human
health, after these drugs are released on the market. The goal is to obtain scientifically based data on
rational and safe use of drugs.
3
, The Institute of Medicine has set up guidelines to better monitor and report on drug safety and they
enforce the FDA/EMA to have authority to demand research from pharmaceutical companies. There
are also black triangles on newly approved drugs so that they know that this drug should be
studied more intensively.
Direct-to-consumer advertising is prohibited in the first few years.
Who has interest in PMS?:
- Patient wants effective and safe drug with reliable information.
- Physician/pharmacist wants reliable and complete information to make a good decision.
- Insurance company importance of rational prescribing with regard to costs.
- Government registration and safety.
- Industry wants a good product.
Data sources for PMS:
- Spontaneous reporting systems. Pharmacovigilance database Lareb pharmacists report
any adverse effect that has not been mentioned earlier. No firm conclusions can be drawn
from this. The report may be a signal for further research. The degree of causality is
determined for each reporting.
- Routine databases (prescription/GP database).
- Questionnaires/interviews/web-based and cohorts/physical testing.
- Lab data.
Because of the new privacy law it is much harder to get medical data from a patient.
Pharmlines Initiative: to link the lifelines cohort study to the prescription data base IADB.
It does not matter much whether you take information from the GP or from the questionnaire
both resulted in more or less the same odds ratio.
ATC coding = Anatomical Therapeutic Chemical classification system.
Classification is done each year by the WHO. They also update the system. There are 7 positions and
5 hierarchical levels.
Level 1: 1 letter refers to the anatomical main group.
Level 2: 2 digits refer to the therapeutic main group.
Level 3: 1 letter therapeutic subgroup.
Level 4: 1 letter therapeutic/chemical subgroup.
Level 5: 2 digits chemical substance.
This coding can be different for the same drug different dosage forms lead to different coding.
What is the defined daily dose (DDD) based on? On the final phase registration trial just before
registration. DDD does not contain patient information it is just a general advise. So for elderly or
children the DDD may not be the right dose. The DDD may vary by country and it simplifies
international comparison of dosage.
You do not have to use the DDD when other drugs interact with it you can even half the dose.
The DDD is the average daily maintenance dose for a drug used for its main indication in adults.
DDDs are mainly used to quantify the volume of drug usage at the population level.
What happens if a patient receives less than 1 DDD when it is a normal adult with the normal
indication? the drug is not as effective as it should be.
When a patient gets more than 1 DDD side effects.
4
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