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Summary Pharmacoepidemiology
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Summary PharmacoepidemiologyPharmacoepidemiology
Epidemiology
What is wrong with these children? (DIAGNOSTICS)
Polio. These children all have polio
What is causing this disease? (ETIOLOGY)
It is a virus that causes its disease. The virus gets on the motor neurons on the children and get
them paralyzed. The virus causes the neurons to dysfunction.
What is the future of this child? (PROGNOSIS)
The paralysis will never go away. It can be a stable disease but most likely it will be a progressive
disease.
What is the “best” treatment? (INTERVENTION/THERAPY) —> Therapeutic intervention
The virus can not be treated. There is no anti-viral drug that can be used to treat the polio. There
can be done physiotherapy to help them to walk better and there can be given painkillers.
How could this be prevented? (INTERVENTION/PREVENTION) —> Preventive intervention
The disease can be prevented by the polio vaccine DTB vaccine (get the vaccine 4 times in a
row).
Economics
How expensive is it to prevent this? (EFFICIENCY/ECONOMICS)
The vaccine is not expensive. It is actually very cheap. It is a cost-effectiveness prevention.
Definition Epidemiology
“Epidemiology is the science that studies the occurrence of diseases in large populations of
people as a function of determinants”.
Epidemiology is an essential science for the conduct of “Evidence Based Medicine”.
Research topics in epidemiology:
Etiology, Diagnostics, Prognostics and Intervention
Etiology/intervention versus diagnosis/prognosis
Etiology/intervention
- Causal association
- Analytic studies
- Case-control/RCT —> Randomized Control Trials
- Mostly 1 determinant (does smoking cause lung cancer —> Yes/no)
- Confounding bias (may happen)
- Explanatory statistical model
Diagnosis/prognosis
- Predictive association
- Descriptive studies
- Cohort design
- More determinants (predicting weather (rain))
- No confounding bias
- Predictive statistical model
Pagina 1 van 132
,Example of intervention: polio in the USA
- NY, June 6th: 2 children (4, 6) presenting with fever/paralysis
- NY, August 15th, 1916: 9000 polio, 2400 died
- 1932 Dr Kolmer: Culturing a chemically weakened virus in bone marrow of monkeys to use as a
vaccine
- Vaccine: 11-/15- year old sons, assistant, 25 children
- 10.000 children vaccinated (40 doses from each monkey, 250 total)
- 1935, St. Louis, meeting: From 10.000 people 10 paralyzed, 5 died by the vaccine. So that was
not very successful.
- 1953, Dr. Salk: mineral oil vaccine, safe vaccine?
- Largest experiment ever, 5 billion dollar
- 420.000 salk vaccine, 200.000 placebo vaccine, 1.2 million without vaccine
- Follow up
- 16 polio cases died, nobody received vaccine:
- 2/36 with severe polio received the vaccine
- Without vaccine 3.3 times higher chance of a polio infection
Polio continued
- Safe?
- “The small number of cases in vaccinated persons, the lack of correlation between site of
paralysis and inoculation, absence of association in time between vaccination and prevalence,
the absence of extension in households, lead uniformly to the conclusion that the vaccine is
safe”.
Meeting: 52.000 doctors, 15 television stations and 150 reporters.
Polio continued
- March 26th , 1955: Lab of biologics contra (precursor of the FDA/EMA): 327k dollar, 10 doctors/
scientists, without experience on polio vaccines, testing 200 products/year:
- Issued: Minimal requirements company fro registration: 5 A4
- “… method which is consistently and series were not defined
- Amount of samples to be tested, inactivation time of virus and inactivation method were not
defined
- In contrast: Salk vaccine trial protocol: 55 A4
Polio continued
- April 12th: five companies licensed < 1 day
- (Now: 12 months, 60.000 A4)
- Cutter laboratories: Famous, but chaotic
- April 25th: first reports of paralysis
- 1/3 lots were unsafe and no documents were reported, because this was not obligatory
- All Cutter vaccines withdrawn from market
- End of April 1955: 380,000 people were already vaccinated
Polio continued
Injuries from Cutter vaccine:
- 220,000 people were infected with polio
- 70,000 muscle weakness
- 164 severe paralysis (75% permanent)
- 10 died due to polio
Pagina 2 van 132
,Polio vaccination Today
- Salk vaccine and Sabin vaccine
- Inactivated and oral vaccine
- Part of worldwide children vaccination program (DKTP Netherlands)
- National vaccination days. In India 150 million were vaccinated in one day
- Incidence reduced from 350,000 patients in 1988 to 33 in 2018
- 1988: WHO polio eradication program
18
MECHANISMS OF DISEASE
Circular model Drug development drug utilization studies pathophysiology
First they try to find out what the pathophysiology economical evaluation
target finding
is of the polio disease. So they found a target and a DRUG DISCOVERY
lead finding and the developed all kind of Post-marketing
Pharmacoepidemiology lead finding
characterization, toxicological evaluation and than Circular model
registration of
they formulated it and did a large-scale production. Drug development
Then they did pre-marketing clinical trials. Finally
mechanisms of action
there is a post-marketing pharmacoepidemiology Pre-marketing
and registration of the product, economical Clinical trials CHARACTERIZATION
evaluation and drug utilization studies. toxicological evaluation
large-scale production
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biopharmacy and pharmacokinetics
(ADME) PharmacoEpidemiolgy
FORMULATION & PharmacoEconomics
(Clinical) Pharmaco-epidemiology
Scientific field that studies the contribution of drugs in disease prevention and therapy in large
populations.
Questions:
There is a COVID-19 vaccine on the market
What do you want to know about the vaccine?
Effectiveness, Safety, Storage, Cost, Production, Side effects, Dose frequency, Mechanism of
action, Long term effect, Cost effectiveness, Accessibility, Prevention of mutations of virus, Effect
in combination with other drugs/diseases, age restriction for usage, Effect on people with
comorbidities, Contra-indications, Target audience.
What are typical research questions?
Does it prevent disease?, Does it prevent infecting another person?, Is it effective in all age
groups?, How many antibodies are necessary for preventing disease?, Is it effective in mutated
viruses?, Who is going to use the vaccines? How long does it provide prevention?
Fields of research in pharmacoepidemiology
- What proportion of the population is using drugs/vaccines?
- Which determinants predict the use of drugs/vaccines?
- Do drugs/vaccines lead to reduction in diseased cases / mortality / increase in quality of life?
- What type of and how many side effects are caused by drugs/vaccines?
Question: Name two drugs that have caused severe adverse reactions?
Thalidomide (softenon), Diethylbestrol, Chloroquine, Diana pil, Opioid pain killer (Oxycodon), Paxil,
Ssri, Sildenafil.
Pagina 3 van 132
, Examples of serious side effects in pharmaco-epidemiology
Year Drug Suspected adverse reaction
1880 Chloroform Heart infarction
1961 Thalidomide (Softenon) Phocomelia, heart defects
1966 Birth control pill (Diana pill) Thrombosis
1984 Valproic acid in pregnancy Spina bifida
1996 Mefloquine Depression, psychosis
1998 MMR vaccine (measles, Autism (fraud paper —> not true)
mumps, rubella)
2004 Statins Myopathy/rhabdomyolysis
2005 Venlafaxine QT prolongation
2008 Rimonabant Depressions
2009 Biphosphonates Osteonecrosis of the jaw
2013: Diane-35
“Since late January the Diane birth-control pill made the headlines, because the French
authorities announced to suspend sale. Since then, the Netherlands Pharmacovigilance Centre
Lareb received heaps of reports on adverse reactions that are thought to be cause by Diane birth-
control pills.
The minister supplied the latest figures, on March 11, 2013 there were 573 reports, including 15
reports of deaths. Most reports were collected after February 1st, 2013 and these reports were
submitted by patients, while mostly physicians report adverse reactions. In total Lareb received 18
reports of death related to third - and fourth-generation contraceptive pills
Label changes (Standard product characteristics)
Withdrawn drugs (1998-2010)
Withdrawn from the market (1998-2010)
- Mibefradil (hypertension) arrhythmia
- Cerivastatin (statin) rhabdomyolysis and acute kidney failure
- Nefazodone (antidepressant) hepatotoxicity
- Rimonabant (anti obesity) Depressions
- Rosiglitazone (anti diabetic drug) Cardiovascular disease
- Depronal (propoxyphene, opioid) Severe adverse effects
- Sibutramine (anti obesity) Severe cardiovascular risks
- (Ro)acutane (Acne drug) Link with birth defects
- Valdecoxib(Bextra) Cardiovascular disease
- Rofecoxib (Vioxx) Cardiovascular disease
Pharmacoepidemiology:
Directive in discussion: justified or not??
Four main reasons for dangerous side effects and withdrawal
1. Clinical trials are not large
2. “Real world” use of a drug differs
Table 1. Number (percentage) of new drugs categorized by the total
3. Time plays a role number of patients in pre-marketing research.
4. Off-label prescribing may bring up unexpected issues
26
Table 1. Number (percentage) of new drugs
categorized by the total number of patients in
pre-marketing research
Duijnhoven RG, Straus SMJM, Raine JM, de Boer A, et al. (2013) Number of Patients Studied Prior to Approval of New Medicines: A
Database Analysis. PLoS Med 10(3): e1001407. doi:10.1371/journal.pmed.1001407
Pagina 4 van 132
http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001407
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PharmacoEpidemiolgy
& PharmacoEconomics
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