Pharmacoepidemiology

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Introduction / definition

Pharmacoepidemiology is the study of the use and effect of drugs in the population and the use of the knowledge gained from this to identify and develop effective therapies.

Etymology: The word is a combination of the Greek words φάρμακον, τό (poison, medicine), ἐπί (about), δημόθεν (from the people) and λόγος, ὁ (the word, the speech).

Pharmacoepidemiology can be seen as a bridge between clinical pharmacology and epidemiology . The focus on drugs comes from clinical pharmacology, which studies the effects of drugs on humans. The methods and approaches used in pharmacoepidemiology stem from epidemiology.

Both experimental (e.g. randomized controlled study ) and non-experimental study designs (e.g. cohort study , case-control study ) are used. Non-experimental studies can be purely descriptive (e.g. studies on drug use) or analytical or both descriptive and analytical. Pharmacoepidemiology examines and describes both positive and negative effects of drugs, medical devices and vaccines. One of their most important tasks is to record rare or unexpected adverse drug reactions as well as effects that only occur after a long latency period (e.g. cancer). The subsequent quantification of the risk in comparison to existing alternatives is one of the greatest challenges in pharmacoepidemiology.

The investigation of adverse drug reactions requires special requirements for the design of pharmacoepidemiological studies. For example, drug exposure (drug exposure) is not always constant: the frequency of prescribing a drug can change, e.g. B. when new drugs are introduced for the same indication or there is new information about existing therapies. The disease itself can affect drug exposure, e.g. B. higher dose with greater severity of the disease. This can influence compliance (therapy adherence), e.g. B. poorer compliance with a slow decline in disease symptoms, or the occurrence of adverse drug effects, e.g. B. by a higher dose. Furthermore, the risk of adverse drug reactions occurring is not constant and can change over the period of treatment.

Pharmacoepidemiology can also support other areas of health sciences , including through knowledge of the frequency and triggers of diseases, the distribution of diseases in the population and the use of health services.

Data basis for pharmacoepidemiological studies

There are numerous data sources that can be used for pharmacoepidemiological analyzes. In general, a distinction is made between primary and secondary data. Each data source has advantages and disadvantages. Therefore, data from multiple sources is often used. A typical example is the linking of study or health insurance data with data from birth, death and cancer registers .

Primary data

Primary data are original data that are collected for a specific research reason. They can be generated in a variety of ways.

In interviews or with the help of structured questionnaires, for example, patients are asked directly about their drug use. They can provide information about which medications (including over-the-counter, so-called OTC drugs , dietary supplements and medication required) they are taking and answer questions about compliance, dosing schedule and tolerability. In order to avoid false information due to incorrect memories ( recall bias ) when recording medication, patients can be asked to bring all their medication with them to the survey (“brown-bag method”). Alternatively, home visits can be made to check patients' medication cabinets. Information from doctors, pharmacists, nurses and other members of the healing and health professions can also be used as a primary data source. In particular, these professional groups can provide information on prescribing behavior, the dispensing and exchange of drugs in the pharmacy, as well as common problems with taking drugs.

In order to be able to collect and evaluate primary data, there must be a positive vote from an ethics committee . In addition, the respondents must agree to the use of the data. Examples of studies that use primary data and are used for pharmacoepidemiological analyzes are e.g. B. the UK Women's Health Initiative (WHI).

Secondary data

Secondary data is mostly collected for administrative purposes or in the context of patient care and not specifically for answering research questions. For pharmacoepidemiological analyzes, routine data from the health insurance companies (billing data), data from patient registers and survey data (survey data) are used in particular .

Statutory and private health insurance companies routinely collect data for the benefit billing of their insured persons. They contain information on all reimbursed services and medicines. Information about the height, weight, lifestyle or laboratory values ​​of the insured is not available. In Germany, the use of health insurance data for research purposes is regulated in Section 75 SGB X. The data is usually evaluated anonymously or pseudonymized. The evaluation can be carried out by the health insurance companies themselves or by research institutes. The Leibniz Institute for Prevention Research and Epidemiology - BIPS conducts research on the basis of the Pharmacoepidemiological Research Database (GePaRD), which contains billing data from four statutory health insurances. Furthermore, the German Institute for Documentation and Information in Health Care ( DIMDI ) provides the “Information System Care Data” from routine data from the statutory health insurance funds for research purposes. Other European databases with secondary data are the Dutch PHARMO and the British CPRD (Clinical Practice Research Datalink).

Also, patient registries such as cancer registers are used as a secondary data source in the Pharmacoepidemiology. These are database systems that have been set up to study specific disease events. The information collected differs depending on the purpose of the register. The doctors usually transmit socio-demographic data, diagnoses, results of laboratory tests and therapies, and drug prescriptions. Suspected adverse drug reactions can also be collected.

In order to monitor the health and health behavior of the population, authorities conduct surveys of representative samples. In Germany, the Robert Koch Institute and the Federal Statistical Office are responsible , and the Statistical Office of the European Union ( Eurostat ) throughout Europe . The survey data serve as an information basis for politics and research and can also be used for pharmacoepidemiological analyzes.

Further potential secondary data sources in pharmacoepidemiology are prescription numbers from statutory health insurances, sales figures from pharmaceutical companies, wholesalers and pharmacies, as well as records from pharmacies of drugs dispensed and patient files. The latter contain information about drug therapies, laboratory data, examinations and patient treatments. The structure and accuracy of the information in patient files depend on the person making the document and are therefore very variable. Another disadvantage is that these documents are not always available electronically and are usually not developed for research purposes. The information it contains may therefore be inaccurate and incomplete.

Limitations of the use of primary and secondary data in pharmacoepidemiological research

In addition to study-specific limitations, the use of primary and secondary data for pharmacoepidemiological studies is generally subject to certain restrictions.

The most important restrictions in the use of primary data are (incorrect) recall of the respondents, especially when they were taking medication or illnesses (recall bias), as well as systematic errors in the selection of the study population (selection bias). Selection bias can also occur when using secondary data for pharmacoepidemiological studies, whereas recall bias is not present for secondary data. Since all information, such as If, for example, diagnoses and prescriptions are recorded directly at the time of the event, secondary data cannot be biased due to incorrect remembering. An important disadvantage of the secondary data is that, depending on the data source, there is no information on factors such as height, weight, smoking status or laboratory tests. In contrast, these can be specifically asked for or measured in primary studies.

Pharmacovigilance (drug safety) in pharmacoepidemiology

As a consequence of the thalidomide scandal , systems for monitoring the safety of drugs ( pharmacovigilance ) were introduced in many countries . Pharmacovigilance is the continuous monitoring of adverse effects and other safety-relevant aspects of drugs that have already been approved. In practice, pharmacovigilance refers almost exclusively to spontaneous reporting systems that enable doctors and other groups of people to report adverse drug reactions to the authorities.

In pharmacoepidemiology, the data obtained by means of the spontaneous reporting systems are evaluated. This examines whether statistically significantly more reports of adverse drug reactions have been received for a specific drug or vaccine than for drugs / vaccines with a similar or the same effect. These evaluations are also called signal generation. A strong inequality can be understood as an indication of a potentially unsafe drug. One also speaks of so-called disproportionality analyzes.

Findings from pharmacovigilance in Germany are communicated to doctors and pharmacists through so-called “ Red Hand Letters ”.

PAS studies (drug safety studies) as part of pharmacovigilance

As part of pharmacovigilance, officially required studies in pharmacoepidemiology on the safety of drugs after their introduction into the drug market, known as the Post Authorization Safety Study (PASS), are carried out.

It is necessary to monitor the safety of drugs even after they have been approved, as certain groups such as children, pregnant women, the elderly and people with multiple diseases are not adequately taken into account in the clinical studies prior to approval. In addition, clinical studies take place under ideal conditions and not in the general everyday care routine. The medical staff is specially trained and no individual treatment patterns are used. In addition, rare and very rare side effects of drugs can only be insufficiently recorded in the context of clinical studies. These adverse drug reactions occur in less than 1 in 1,000 to 10,000 users.

Even before approval is granted, pharmaceutical manufacturers must discuss in the context of a risk management plan which measures they are taking to reduce risks and which studies they want to carry out on the safety and effectiveness of the drug. PASS can therefore be carried out voluntarily by the pharmaceutical manufacturer in order to review the measures of the risk management plan or as a requirement of the authorities upon approval. Both clinical and non-interventional studies, also called observational studies , can be carried out. The data from secondary databases are often used to carry out non-interventional PASS. All PASSs carried out in Europe can be viewed in the register of the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP®).

Teaching

Many universities, both in Germany and internationally, offer pharmacoepidemiology as a subject as part of their pharmacy and medical studies. It is also part of the epidemiology master’s courses in Berlin, Bremen, Mainz and Munich. Most of the epidemiologists do their doctorate after graduation. A specialization in pharmacoepidemiology is also possible.

Institutes

There are many opportunities to research pharmacoepidemiology around the world: in the USA, e.g. B. at the Harvard TH Chan School of Public Health or UNC Gillings School of Global Public Health, in Germany, z. B. at the Leibniz Institute for Prevention Research and Epidemiology - BIPS, and in the Netherlands, z. B. PHARMO.

Professional societies

In Germany there are several large specialist societies that deal with the subject of pharmacoepidemiology. The German Society for Medical Informatics, Biometry and Epidemiology eV ( GMDS ) promotes teaching, research and health care. Using documentary, informational, biometric and epidemiological methods, all medical specialist groups are addressed and represented in appropriate working groups. Likewise, the Society for Drug Application Research and Drug Epidemiology and the German Society for Epidemiology eV ( DGepi ) are independent scientific specialist societies that represent epidemiology in research in Germany. Internationally, pharmacoepidemiology is represented in research and at conferences by the International Society for Pharmacoepidemiology (ISPE).

Current studies / important findings

Reassessment of the benefit-risk balance of metoclopramide-containing medicinal products

In 2013, the European Medicines Agency (EMA) initiated a reassessment of the risk-benefit ratio of medicines containing metoclopramide. The background to this was the known risk of severe cardiovascular and neurological side effects such as extrapyramidal symptoms and irreversible tardive dyskinesia .

With the implementation decision of the EU Commission and the corresponding decision of the Federal Institute for Drugs and Medical Devices ( BfArM ) of April 9, 2014, this recommendation has now been legally implemented. It provides for a change in the approval. Products that exceeded certain active ingredient limits were withdrawn from the market. For medicinal products containing metoclopramide that comply with the limit value, the information for healthcare professionals and instructions for use have been changed.

Reassessment of the benefit-risk balance of vaccination against measles, mumps, rubella and chickenpox (varicella)

Pharmacoepidemiological studies have made an active contribution to the safety of vaccinations against measles, mumps, rubella and chickenpox (varicella). A study from Germany has shown that the use of a combined vaccine against all four diseases (MMRV) as an initial dose compared to a vaccination against measles, mumps and rubella ( MMR ) or vaccinations against MMR and chickenpox (V) administered at the same time increased risk of febrile convulsions. Studies from other countries such as the USA also showed an increased risk of febrile seizures when MMRV was administered as the first vaccine dose compared to MMR or MMR + V. Based on these findings, the vaccination recommendations of the Standing Vaccination Commission (STIKO) at the Robert Koch Institute were changed so that MMRV should only be administered as a second vaccination dose. The summary of the product characteristics (product information ) and the package insert from the manufacturer of the vaccine have also been changed to include a warning about the risk of convulsions.

literature

See also

Web links

Individual evidence

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  3. ↑ a b Tatiana Chama Borges Luz, Evalil Nilsson: Drug utilization research: methods and applications . Ed .: Monique Elseviers, Björn Wettermark, Anna Birna Almarsdóttir, Morten Andersen, Ria Benko, Marion Bennie, Irene Eriksson, Brian Godman, Janet Krska, Elisabetta Poluzzi, Kstja Taxis, Vera Vlahovic-Palcevski, Robert Vander Stichele. Wiley-Blackwell, Chichester, West Sussex, ISBN 978-1-118-94977-1 .
  4. ^ A. Nathan, L. Goodyer, A. Lovejoy, A. Rashid: 'Brown bag' medication reviews as a means of optimizing patients' use of medication and of identifying potential clinical problems . In: Family Practice . tape 16 , no. 3 , ISSN  0263-2136 , p. 278-282 , PMID 10439982 .
  5. ^ WHI - WHI Home. Retrieved October 22, 2018 (American English).
  6. ↑ Irene Eriksson, Luisa Ibanez: Drug utilization research: methods and applications . Ed .: Monique Elseviers, Björn Wettermark, Anna Birna Almarsdóttir, Morten Andersen, Ria Benko, Marion Bennie, Irene Eriksson, Brian Godman, Janet Krska, Elisabetta Poluzzi, Kstja Taxis, Vera Vlahovic-Palcevski, Robert Vander Stichele. Wiley-Blackwell, Chichester, West Sussex, ISBN 978-1-118-94977-1 .
  7. ↑ § 75 SGB X transmission of social data for research and planning - dejure.org. Retrieved October 22, 2018 .
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  9. ↑ Supply data . Retrieved October 22, 2018 .
  10. ↑ PHARMO Institute for Drug Outcomes Research. Retrieved October 22, 2018 (American English).
  11. ^ Clinical Practice Research Datalink. Retrieved October 22, 2018 .
  12. ↑ RKI - Health Monitoring. Retrieved October 22, 2018 .
  13. ↑ Home - Federal Statistical Office (Destatis). Retrieved October 22, 2018 .
  14. ^ Post-authorization safety studies: questions and answers | European Medicines Agency. Retrieved October 23, 2018 .
  15. ↑ EMA: PASS. Retrieved October 22, 2018 .
  16. ↑ European Network of Centers for Pharmacoepidemiology and Pharmacovigilance: European Network of Centers for Pharmacoepidemiology and Pharmacovigilance. Retrieved October 22, 2018 .
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  21. ^ Program in Pharmacoepidemiology. Retrieved October 23, 2018 (American English).
  22. ^ Pharmacoepidemiology Research • UNC Gillings School of Global Public Health . In: UNC Gillings School of Global Public Health . ( unc.edu [accessed October 23, 2018]).
  23. ↑ Home . October 8, 2018 ( bips-institut.de [accessed October 23, 2018]).
  24. ↑ PHARMO Institute for Drug Outcomes Research. Retrieved October 23, 2018 (American English).
  25. ↑ German Society for Medical Informatics, Biometry and Epidemiology (GMDS) eV: GMDS e. V. Retrieved October 23, 2018 .
  26. ^ The DGEpi »German Society for Epidemiology. Retrieved on October 23, 2018 (German).
  27. ↑ International Society for Pharmacoepidemiology (ISPE) pharmacoepi.org - International Society for Pharmacoepidemiology. Retrieved October 23, 2018 .
  28. ↑ European Medicines Agency recommends changes to the use of metoclopramide | European Medicines Agency. Retrieved October 23, 2018 .
  29. ↑ BfArM - Risk assessment procedure - Metoclopramide-containing drugs: Implementation of the implementation decision of the EU Commission. Retrieved October 23, 2018 .
  30. ↑ Tania Schink, Jacob Holstiege, Frank Kowalzik, Fred Zepp, Edeltraut Garbe: Risk of febrile convulsions after MMRV vaccination in comparison to MMR or MMR + V vaccination . In: Vaccine . tape 32 , no. 6 , February 3, 2014, ISSN  1873-2518 , p. 645-650 , doi : 10.1016 / j.vaccine.2013.12.011 , PMID 24374498 .
  31. ↑ Steven J. Jacobsen, Bradley K. Ackerson, Lina S. Sy, Trung N. Tran, Tonia L. Jones: Observational safety study of febrile convulsion following first dose MMRV vaccination in a managed care setting . In: Vaccine . tape 27 , no. 34 , July 23, 2009, ISSN  1873-2518 , p. 4656-4661 , doi : 10.1016 / j.vaccine.2009.05.056 , PMID 19520201 .
  32. ↑ Nicola P. Klein, Bruce Fireman, W. Katherine Yih, Edwin Lewis, Martin Kulldorff: Measles-mumps-rubella-varicella combination vaccine and the risk of febrile seizures . In: Pediatrics . tape 126 , no. 1 , ISSN  1098-4275 , p. e1-8 , doi : 10.1542 / peds.2010-0665 , PMID 20587679 .
  33. ↑ Epidemiological Bulletin September 26, 2011 / No. 38 . ( rki.de [PDF; accessed on October 23, 2018]).