Pharmacoepidemiology

1. Pharmacoepidemiology is defined as the study of the use and the effects of drugs in large groups of people. It can be viewed as an epidemiological discipline with particular focus on drugs. JAMASOFT2017

2. The scandinavians pioneered the developement of methods to study drug utilisation. JAMASOFT2017

3. More than 100,000 pharmaceutical packages are licensed in European countries and tons of medicines are daily used with a yearly expenditure wider than 100 billion euro. JAMASOFT2017

4. This very large amount of medicines is a challenge to public health for several reasons: JAMASOFT2017

5. Medicines can positively influence public health by their intended therapeutic effect. Medicines can adversely affect public health because of medicine related problems; medicines related problems are an important cause of mortality and most of them can be prevented. There is an important economic burden of medicines on healthcare systems. Medicines are able, via the wastewater, to pollute the environment, including drinking water. Several medicines have endocrine-disrupters or carcinogenic properties. There are wide discrepancies between European countries in licensed medicines and in their price, utilisation and expenditure. JAMASOFT2017

6. Because of these challenges of medicines on public health there is a need JAMASOFT2017

7. to increase awareness and spread knowledge on the impact of medicine utilisation onpublic health to promote European harmonised data collection about licensed medicines, their prices, utilisation and expenditure, to develop indicators for monitoring price, utilisation and expenditure of medicines at a European level to promote benchmarking exercise on utilisation of medicines at national and regional level to assess the outcome of medicine utilisation, linking pharmacoepidemiological data to morbidity-mortality data to develop a public health-oriented European database of the licensed medicines with relevant information about their best use JAMASOFT2017

8. For all these purposes it is essential to have an internationally valid classification system of medicines and a measurement system of their utilisation. JAMASOFT2017

9. Since 1981, the WHO Regional Office for Europe has recommended the ATC (Anatomical Therapeutic Chemical) classification system and the DDD (Defined Daily Dose) as the standard for medicine classification and drug utilisation studies, respectively. JAMASOFT2017

10. Since 1996 the ATC/DDD methodology has been adopted and proposed by the WHO Headquarters for global use. JAMASOFT2017

11. Minimal Data Set for National Register of Medicinal Products with Validated ATC Codes and DDD Values JAMASOFT2017

12. The Register should contain at least the following elements (in separate fields): 1. Registration number or other unique identifier 2. ATC code 3. Active ingredient(s) 4. Medicinal Product Name with its specifiers 5. Trade Name 6. Pharmaceutical Form 7. Strength 8. Pack size 9. Legal category 10. Reimbursement 11. Pharmacy retail price 12. Date of approval 13. Date of first marketing 14. Date of removal from the market 15. Holder of marketing authorisation 16. Generic 17. Parallel import 18. Value of the DDD 19. Route of administration 20. Number of DDDs in the pack JAMASOFT2017

13. Registration (Marketing authorisation) number or other unique identifier JAMASOFT2017

14. Allowed format: letter, number or alphanumeric code [text]. Length: >6 Definition. The registration number can be defined as a code representing the market authorisation act within a given marketing authorisation territory. No definition of registration number is given in the rules governing medicinal products for human use in the European Union. A code must be used once and it cannot be repeated in the file. If a pack is withdrawn from the market the number cannot be used for a new licensed product. It can be an advantage when more national registers use the same number [i.e. the Nordic number] for the same package. JAMASOFT2017

15. ATC code Allowed format: alphanumeric code [text]. Length: max 7 characters Definition. See separate description in paragraph 6 - ATC and DDD linkage process. Examples: C09AA01; C03AA01; B01AC06 JAMASOFT2017

16. Active ingredient 1 • Allowed format: text • Definition. Ingredient that alone or in combination with one or more other ingredients is considered • to fulfil the intended activity of a medicinal product. • Nomenclature. International non-proprietary names (INN) should be used. If INN names are • not assigned, USAN (United States Adopted Name) or BAN (British Approved Name) names • should be used. If the product contains more than one active ingredient it is recommended that the • description stops to the first three ingredients. In this case the names of the active ingredients • should be given in the same order of the “ATC INDEX with DDD” JAMASOFT2017

17. Active ingredient 2 For a second active ingredient in the case the medicinal products contains more than one active ingredient JAMASOFT2017

18. Active ingredient 3 For a third active ingredient in the case the medicinal products contains more than one active ingredient JAMASOFT2017

19. Further active ingredients Allowed format: yes/no If the package contains more than the three active ingredients given in the fields above, this should be indicated in this field, without further description of these additional active ingredients JAMASOFT2017

20. Medicinal Product Name with its specifiers Allowed format: Text Definition. Medicinal Product Name Specifiers are the additional elements added to the medicinal product name in order to distinguish medicinal products with the same medicinal product name. The additional elements can be based on: • the galenic properties (enteric coated, slow release, CR) • a strength related property (by means of an imprecise term (Forte, Mitis) or by means of an indication related to the amount of active ingredient (Transderm Nitro 5, Humelin 60/40) • an intended user group (paediatric, geriatric) • the ingredients, mainly the reference active ingredient (Rubella live vaccine) • the physical nature of the product • the route of administration (Oral gel; Oral Tablets; Intravenous solution) • the pack size (28 tablets; These elements should be treated as an integral part of the medicinal product name for identification purposes. Directive 92/27 EEC indicates specifiers to add to the medicinal product name e.g. strength and pharmaceutical form Examples: Capoten tablet 50 mg 28-tab pack Lasix injectable solution 10 mg/mL ampoule 2 mL Canesten cream 1% tube 50 g JAMASOFT2017

21. Trade Name Allowed format: text Definition. Name given for marketing purposes to any ready-prepared medicinal product placed on the market under a special name and in a special pack. A trade name may be a protected trademark. (Synonyms: Brand name; Innovator’s name; Fantasy name; Proprietary product name; Pharmaceutical speciality product name; Medicinal speciality product name) Examples: Lasix, Canesten, Berotec, Captopril GNR, etc. JAMASOFT2017

22. Pharmaceutical Form Allowed format: text Definition. The Pharmaceutical Form is the combination of the form in which a medicinal product is presented by the manufacturer (form of presentation) and the form in which it is administered including the physical form (form of administration). JAMASOFT2017

23. Strength 1 (value) Allowed format: number; two decimal digits. Definition. Designation based on the composition of one or more pharmaceutical products in a medicinal product. The strength of a medicinal product is simply an expression of an identifying characteristic based on its composition. Strength will not normally be given for multiple ingredient medicinal products with more than three ingredients. Non-standardised expressions of strength are often used in addition to a trade name or a generic name (forte, paediatric, super, plus) but this should be avoided. JAMASOFT2017

24. The ATC and DDD methodology isnow a widely accepted consensus on how to categorise drugs and compare sales of drugs of different potency. JAMASOFT2017

25. The background of pharmacoepidemiology istheincreasingunderstandingthattheinformationgathered in pre-marketingstudiesdoesnotadequatelydescribethetruehealthimpactof a drug. There are tworeasons: JAMASOFT2017

26. First pre-marketing trials are usually conducted in highly selected populationsfree of concurrent ailments or drug use, and who very poorly represent the drug users after marketing. JAMASOFT2017

27. Secondly most drugs have important side effects that are not known at the time of marketing, either because they are too rare to be noticed in the small premarketing trials, or they are confused with unrelated, randomly occurring adverse events. JAMASOFT2017

28. Scandinavians pioneered the development of models to study druguse in populations, mainlythroughtheworkoftheDrugUtilizationResearchGroup (DURG) undertheauspicesof WHO. Twoinventionswerecrucialforthisaccomplishment: JAMASOFT2017

29. The first is a hierarchical system to classify drugs, the Anatomical-Therapeutic-Chemical (ATC) code. JAMASOFT2017

30. The other important development for the study of drug use in populations is the defined daily dose (DDD). JAMASOFT2017

31. The DDD is established by an international expert panel as the typical maintenance dose for a drug when it is used by an adult for its main indication. The DDD for two different drugs should thus in principle express equipotent doses. A few illustrative examples are shown in next table: JAMASOFT2017

32. JAMASOFT2017

33. The DDD should not be interpreted as a dose recommendation, but rather as a technical unit of measurement that allows us to collapse data on drugs with differing potency. JAMASOFT2017

34. As an illustrative example:the ATC code for ibuprofen is shown in next scheme: JAMASOFT2017

35. ATCcode has 5 levelsand7 digits. The first level, the M, indicates that the drug belongs to the class of drugs with action on the muskulosceletal system. The next level, indicated by 01, specifies it further as belonging to the group of anti-inflammatory drugs, the next level A as an NSAID (non-steroidal anti-inflammatory drugs) etc. JAMASOFT2017

36. This classification provides a consensus about how to collapse drugs with similar properties. By referring to, e.g., NSAIDs as any drug with an ATC-code of M01A in the first four digits, a researcher can avoid endless explanations of whatparticular drugs are the focus of a study of NSAID use. JAMASOFT2017

37. The ATC - System is not theonlypossibleway to classifydrugs, but itprovides a well-elaborated, well-accepted, reasonableconsensus. JAMASOFT2017

38. One recent example of the latter: is the propensity of SSRIs (Selective serotonin reuptake inhibitors (SSRIs) are antidepressants) to cause ulcer bleeding. These limitations warrant the continuous post-marketing surveillance of drug dispersion in society and of drug effects, the two core elements in the definition of pharmacoepidemiology. JAMASOFT2017

39. Both, the ATC system and the DDDs are reviewed once annually by the WHO Collaborating Centre for Drug Statistics Methodology in Oslo, to adjust for new developments in the clinical use of the drugs. JAMASOFT2017

40. DRUGS AS CAUSES OF DISEASE As in most other disciplines of epidemiology, we deal with multiple causes of disease. It is almost an axiom that there are no disease entities where drug exposure is both a necessary and sufficient cause. There may be observed that a patient developed some unexpected adverse event after starting a drug, but he can never conclude with certainty that the drug caused the event. JAMASOFT2017

41. This possibility of confusing adverse drug reactions with other adverse events entails two categories of problems: • a delay in the recognition of true adverse drug reactions, • or perceiving something as adverse drug reactions when in fact it is not. JAMASOFT2017

42. There are many examples of the former. E.g., aspirin was marketed in 1898. Gastroduodenal lesion ascribed to aspirin was not described before 1939. Not before the early 1970s, more than 70 years after marketing, could it be viewed as well documented that these lesions exist.Phenacetin was marketed in late 1890s, but its liability to cause renal failure was not reported before 1955. JAMASOFT2017

43. The other category of problems, perceiving something as adverse drug reactions when in fact it is not, is seen when old doctrines, e.g., the depressiogenic effect of betablockers, is subjected to formal testing and found to be not substantiated. JAMASOFT2017

44. Today we have a hierarchy of available designs: JAMASOFT2017

45. PHARMACOEPIDEMIOLOGIC DATABASES Oneofthemainmethodologicaldevelopments in pharmacoepidemiology has beentheemergenceoflargedatabaseswith more or lesscompletecaptureofindividualdruguse and clinicaloutcomesforlargepopulations. JAMASOFT2017

46. PHARMACOEPIDEMIOLOGIC DATABASE Itmakesitpossible to gatherdetailedsystematicinformation on largegroupsofdrugusers and to linkittoinformationconcerningsuspectedadverseoutcomes in individualusers. JAMASOFT2017

47. The advantages of using pharmacoepidemiologic databasesare: • Data are free of recall or interviewer bias.A statistical sampling or testing error caused by systematically favoring some outcomes over others.) 2. Data are already recorded when the controversy arises. 3. Costs are usually low. JAMASOFT2017

48. The most important limitations of pharmacepidemiologic databases are: 1. They are not suitable for the study of drug effects where the timing of drug intake is critical, i.e., short-term hyperacute effects. 2. It may be uncertain whether the patient has actually ingested the drug. 3. Cases where the endpoint is poorly described by the coding system. 4. They do not cover medication bought over the counter. JAMASOFT2017

49. CONCLUSIONS Pharmacoepidemiology is the study of the use of and the effects of drugs in large groups of people. There are worldwide a number of databases with comprehensive registration of drug use and outcomes for entire populations. JAMASOFT2017

50. CONCLUSIONS • Pharmacoepidemiology allows to make comparisons between countries and regions (drug utilisation studies). JAMASOFT2017