Unit 1 pharmacoepidemiology

Definition and scope of pharmacoepidemiology

1. Definition and Scope of Pharmacoepidemiology By Dr. Supriya Suman

2. Definition 01 Origin and Evaluation 02 Need 03 Aims and Application 04 Topics to be Cover

3. Definition

4. Pharmacoepidemiology is the study of the use and effects of drugs in large numbers of people. It is a growing discipline that applies epidemiological techniques to study drug use in a large population. Just as the term implies, pharmacoepidemiology combines clinical pharmacology with epidemiology.

5. Pharmacology is the study of the effects of drugs Clinical Pharmacology is the study of effects of drugs in humans Epidemiology is the study of the distribution and determinants of disease in populations Pharmacoepidemiology is the study of the use of and effects of drugs in large numbers of people

6. Origin and Evaluation

7. John Snow: English Physician (1813-1858) Add Skills – 90% Father of modern epidemiology Spot map illustrates cases of cholera centered around pump Statistics illustrate connection between quality of water source and cholera cases Study was major event in public health history Name Here A spot map was drawn to illustrate how cases of cholera were centered around one pump

8. 400BC 1854 1865 Father of modern medicine Coined the term ‘endemic’ Hippocrates promoted clean hands for wound management Hippocrates Father of modern epidemiology work in tracing the source of a cholera outbreak in Soho, England John Snow Introduced mathematical methods in epidemiology Early 20 th Ronald Rose & his team British Surgeon Discovered antiseptic (carbolic acid)as an antiseptic by applying Louis Pasteur’s advances in microbiology Molecular epidemiology focusing on relationship between biomarker and disease evolved Later 20 th 20 th Century J oseph Lister

9. Initially there were no regulation to ensure the safety and efficacy of drugs available in the market. In 1906 US govt passed pure food and drug act in response to excessive adulteration & misbranding of food and drugs. In 1937 ,over 100 of people died from renal failure as a result of the elixir sulfanilamide dissolved in diethylene glycol. In 1938 D&C act was passed ,because of this manufactures enquired an approval from FDA before marketing a drug.

10. Thalidomide Tragedy Add Skills – 90% Marketed as safe , non barbiturate hypnotic in Britain in 1958. In 1961,at a congress of gynaecologists attention was drawn to the birth of a large number of babies with congenital abnormalities ,which was previously rare. A retrospective study of 46 mothers delivered of deformed babies showed that 41 were found to have thalidomide during their early pregnancy. This was compared with a control of 300 mothers who had delivered normal babies ; none of these had taken thalidomide. Laboratory experiments confirmed that thalidomide was teratogenic in experimental studies. Over 10,000 children were born with thalidomide-related disabilities worldwide(Phocomelia)

11. Current status of Thalidomide In 1964 a leprosy patient was given thalidomide when other tranquilisers and painkillers failed. The doctor noticed the drug also reduced other leprosy symptoms. Research into thalidomide’s effects on leprosy resulted in a 1967 WHO clinical trial. Positive results saw thalidomide used against leprosy in many developing countries. It is also used successfully in Multiple myeloma, Type 2 leprosy reaction. With black box warning (can cause severe birth defect or embroyfetal death even with 1dose) The renewed use of thalidomide remains controversial.

12. In 1960s UK established a “Committee on Safety of Drugs”(CSD). Yellow card started by CSD in 1964 In 1968 UK established a committee on safety of medicine. WHO established a bureau to collect and analyze information from this and similar national drug monitoring organizations. In early 1960, the related field of drug utilization was developed along with the study of ADRs With all these development 1960’s considered to be the beginning of field of pharmacoepidemiology.

13. . ISPE (International Society for Pharmacoepidemiology) was formed to obtain more data on risk & benefits of drugs in population and to discuss, develop & disseminate information about pharmacoepidemiological methods Launched officialy in 1989 during 5 th – International Conference on Pharmacoepidemiology in USA. It is the forum for the exchange of scientific information and development of education policies in the field of Pharmacoepidimiology . Activities related to: Pharmacovigilance Drug utilization research and Outcome research Comparative effectiveness research Therapeutic risk manageme nt

14. Need for Pharmacoepidemiology

15. Pharmacotherapy safe and effective The study conducted during the development process and approval of the drug product Involve 3000- 4000, may have been exposed to the drug Efficacy, Safety, and Risk relies on:- Risk Benefits https://academic.oup.com/biomedgerontology/article/67A/2/181/554540 67A /2/181/554540

16. Limitations of Premarketing Clinical Trials Short duration Premarketing studies are limited in time. Effects that develop following chronic use or those that have a long latency period cannot be detected. Narrowly defined population Premarketing studies generally do not include special populations such as children, women of childbearing age, or the elderly. Limited comparison groups The comparison group is often limited to placebo Small sample size Few drugs are studied in more than 4,000 subjects before FDA approval. Effects that occur with a frequency of less than 1/1,000 are difficult to detect. Narrow set of indications Manufacturers pursue specific indications for use during premarketing studies.

17. Consequences of Limitations of Pre-marketing Trials Benefits Risk Black Box Warnings About 20% of drugs get new “black box” warnings after marketing DRUG WITHDRAWAL About 4% of drugs are ultimately withdrawn for safety reasons https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740994/

18. Result of Pharmacoepidemiological studies Withdraw suspended Precaution & contraindications Black box warning Suicidal tendency increased tendency associated to the use of fluoxetine and other SSRI antidepressants Tardive dyskinesia associated with long-term use of metoclopramide and many antipsychotic Stroke or heart attack associated with sildenafil ( Viagra ) when used with Nitroglycerin Cerivastatin . Treatment of hypelipdeimeia : Introduced in 1990s, withdrawn in 2001..”Why “? , 52 deaths were reported from rhabdomyolysis and its resultant renal failure The story of thalidomide is well known Chloramphenicol and Grey Baby Syndrome Gynaecological cancer in offspring of women receiving Diethyl Stilboestrol Oculomucocutaneous syndrome with practolol Liver disease from benoxaprofen Valvular heart disease from Dexfenfluramine Cardiac arrhythmias with terfenadine

19. Since Pharmacoepidemiology is considered as a science of understanding of medicine, safety issues, all those who use, prescribe, study, monitor or deal with medicine at academic ,research or regulatory level need, Pharmacoepidemiology. Person who needs Pharmacoepidemiology

20. Aims of Pharmacoepidemiology

21. Aim of Pharmacoepidemiology Risk Quantification Spontaneous Reporting System Signal Generation 2 main aspects: The study of adverse effect of drugs The appropriate use of medicines. Hypothesis testing

22. Signal Generation Most commonly information on a possible casual relationship between AE and Drug or Medication relationship. Identify new or serious type of ADR Help to identify new application for existing Drugs. Example: Aspirin Minoxidil https://academic.oup.com/view-large/8797250

23. A Spontaneous Report is an unsolicited, voluntary ,communication from the side of users of medicine or health care professional who know or inform about the AE of a drug It is the one of the most popular methods for signal identification and ADR reporting. Identification of new finding Encourage reporting any reactions suspected be an ADR It helps in promoting culture of reporting useful Pharmacovigilance studies. Spontaneous Reporting System

24. A Risk Quantification is the process of evaluating risks In Pharmacoepidemiology various measures of risk are used examples:- Cumulative incident Incident rate Relative risk Odd ratio Incidence rate ratio Event cannot occur:- given probability “0”, Event can occur:- “1”(uncertain risk is assigned between 0 and 1 maximum ) Encourage reporting any reactions suspected be an ADR Risk Quantification of ADR rates often require large sample size. Risk Quantification

25. In Pharmacoepidemiology Hypothesis testing involve the use of comparison group to determine whether there are difference in variable of interest (risk factor, trait, characteristic, drug exposed, or clinical conditions) Statistical methods are used to assess whether the observed difference could have occur by chance or not. Conclusions about relation b/w exposure to a drug and clinical event thus based on the ability to reject or accept the null hypothesis, postulating that the 2 group are having difference or not. Hypothesis testing

26. Steps of Hypothesis testing:- Formulate H & H a Use Statistic test Compute the p-value Compare p-value with α 01 02 03 04 H The result is by pure chance H a The result show real effect combined with a component of chance variation. Formulate H & H a The smaller the p-value ,the stronger the evidence against the Null Hypothesis. Compute the p-value Identify a test statistic that can be used to assess the truth of the null hypothesis. Use Statistic test If p-value is smaller than significance value the observed effect is statistically significant, the null hypothesis is rule out and alternative hypothesis is valid. Compare p-value with α

27. Signal identified via spontaneous reporting confirmed by a formal Pharmacoepidemiology study Background Phenylpropanolamine (PPA)- ingredient used in OTC and prescription cough and cold medications as a decongestant, and in OTC weight loss products. In 1984, FDA received reports of Hemorrhagic stroke (bleeding into brain or into tissue surrounding brain) in association with PPA. In addition, there were published reports in literature Question-Is the use of PPA-containing products associated with hemorrhagic stroke? AIM of Pharmacoepidemiology Example:-

28. Approach- To confirm this signal, a case-control study was conducted Results The study demonstrated a statistically significant increased risk of hemorrhagic stroke among both appetite suppressant users and first-time users of PPA as cough/cold remedy. Outcome FDA Advisory Committee meeting discussed the case-control study and recommended that PPA be considered not safe for OTC use FDA then took steps to remove PPA from all drug products and requested all drug companies to discontinue or reformulate PPA containing products. Example:-

29. Study Designs

30. Application of Pharmacoepidemiology Post marketing surveillance Efficacy and Effectiveness Pharmacovigilance Drug Usage Analysis Farming of Health & Drug Policies Evaluation of Formulary Systems Drug Information & Patient Care Age based Medicine Use and its Analysis Pharmacoeconomic Analysis Empowering Pharmacogenetics Studies Evaluation of Hospital Committees

31. Post Marketing Surveillance PMS is the practice of monitoring safety of :- Pharmaceutical drug Medical device Pharmacovigilance is the important part of the science of PMS Others:- Off-label drug use Problems with orphan drugs, Lack of Paediatric population New drug –approved-CT- small no.; not with other condition but PMS confirm or deny the safety of the drug in large no.; pts with comorbidity. Used method:- Spontaneous reporting database (INDIA – VIGIFLOW,FORMS). Prescription event monitoring. Patient register & case sheet Health record After market release

32. Post Marketing Surveillance USA :- FDA (MedWatch) Canada: Health Canada(MHPD) Australia: TGA (Blue card ) UK : MHRA (Yellow Card) India: CDSCO ( Vigiflow , ICSR)

33. Efficacy and Effectiveness Difference between efficacy and effectiveness ? Does the treatment work:- efficacy Does the benefits of the treatment outweighs its liabilities for those to whom it is offered for treatment – effectiveness. Efficacy:- RCT Effectiveness- Pharmacoepidemiology Negative outcome – ADR and AE

34. Pharmacovigilance

35. Drug Usage Analysis Medicine usage pattern Identify :- over use, under use ,and non-use of medicines. Study report – serve as a barometer – future study – help to predict changes in the usage.

36. Pharmacoeconomics Analysis

37. Farming of Health & Drug Policies

38. Pharmacogenomics Studies

39. Evaluation of Formulary System With Pharmacoepidemiological Studies:- evaluate the effects of Formularies like Hospital Formulary, State formulary or National formulary to promote rational prescription and usage pattern in the country. Formulary plays an important role in Promoting generic prescriptions.

40. Evaluation of Hospital Committees

41. Drug Information and Patient Counselling

42. Age based Medicine use and its Analysis

43. Thank You Insert the Sub Title of Your Presentation