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1. Health System Research ASMA GHULAM MUSTAFA Faculty of pharmacy University of Lahore

2. Health System Research HEALTH SYSTEM: “All the organizations, people and actions whose primary intent is to promote, restore or maintain health.” WHO 2000 HEALTH SYSTEM RESEARCH: “The multidisciplinary field of scientific investigation that studies how social factors, financing systems, organizational structures and processes, health technologies, and personal behaviors affect access to health care, the quality and cost of health care, and ultimately health and well-being. Its research domains are individuals, families, organizations, institutions, communities, and populations .” 2

3. Primary Concern and Objective of HSR Prime concern of HSR is to provide information for decision-making that can improve the functioning of the health system . The main objective of HSR is to provide health managers at all levels, as well as community members, with the relevant information they need to make decisions on health-related issues and problems they are facing with the aim to improve health system for a health society 3

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5. Types of Research 5

6. Types of Study Design 6

7. Descriptive Case Studies Case Report: The case report is the presentation of the experience of a single patient. It is usually presented in a way that supports a hypothesis or an answer to a question of interest. Case reports are often referred to as hypothesis-generating because these bring forth evidence that supports a hypothesis or conclusion. For example, the presentation of the medications for a patient that were administered until the development of anemia might suggest that one or more of these drugs could have caused the anemia. Case Series: When the common experiences of more than one patient are presented , this is referred to as a case series . Obviously, the greater the number of common experiences, the stronger the evidence to support a conclusion. For example, if five patients developed anemia after exposure to the same medication, this would raise suspicion beyond that for only one such patient . 7

8. Descriptive Case Studies Advantages Useful for hypothesis generation Informative for very rare disease with few established risk factors Usually of short duration . Use to study ADRs of Drugs Disadvantages Cannot study cause and effect relationships Cannot assess disease frequency 8

9. Descriptive Case Studies Ecological study : An ecological study is an observational epidemiological study in which data is analyzed at the population or group level rather than at the individual level. It examines the relationship between exposure and outcome across different groups or populations . For example The relationship between air pollution and respiratory diseases across different cities . Cross-Sectional Study Design: This is a study conducted to obtain the prevalence of an outcome in a given set of patients such as those being treated with a drug at a single time point. Cross-sectional studies are often referred to as snapshot studies. Because data are collected all at once, the temporal relationship between the use of the drug and the outcome of interest cannot be determined in cross-sectional studies. 9

10. Descriptive Case Studies Advantages: Best for determining the prevalence Relatively inexpensive Disadvantages: Only a snapshot at a time leading to a misinformation Response rate may be low ,with result not representative of the population 10

11. Analytical Explanatory Studies Two basic designs: Case – control study Cohort Study NOTE There must be a comparison group 11

12. Case-Control Study 12

13. Case-Control Study A group of affected people is compared to unaffected people(the control) Subjects are selected based on a particular outcome and a study backwards in time to try to detect the causes or risk factors that may have earlier been reported in a descriptive study Subjects are then matched and assigned into the two groups. Subject selected on the basis of disease [ e.g lung cancer]. Sometimes called a retrospective study because of the direction of study . ADVANTAGES: It is relatively easy to carry out because we go back to existing records in the hospital It is also rapid and inexpensive It requires comparatively few subjects There is no risk to the subject DISADVANTAGES It introduces bias To select an appropriate control could be difficult It may be difficult to distinguish between the cause of a disease and an associated factor 13

14. Cohort study 14

15. Cohort study A cohort study is a study in which a group of exposed subjects and a group of unexposed subjects are followed over time to measure and compare the rate of a disease or an outcome of interest in both groups. A cohort study can be prospective (most common) or retrospective. Subject selected on the basis of exposure [etiological factor; cigarette smoking] Follow-up over a period to compare the outcome ADVANTAGES There is less risk of bias ness It allows the study of the natural history of the disease It assists in determining the temporal relationship between the etiological factor & the disease DISADVANTAGES It takes a long time It is expensive Large no of subjects are needed 15

16. Retrospective VS Prospective Cohort Study 16

17. Experimental Studies In a typical experimental study design, the investigator assigns subjects to the intervention and control/comparison groups in an effort to determine the effects of the intervention Studies in which 1 group is deliberately subjected to an intervention compared with a control group with no similar intervention The gold standard in medicine because it proves causality Can be controlled or uncontrolled 17

18. Randomized Control Trials 18

19. Randomized Control Trials RCTs are considered the gold standard of experimental study designs in pharmacy practice. The experimental group receives the treatment or intervention (e.g., a new drug or pharmaceutical care for treatment of a certain disease), while the control group receives a placebo treatment, no treatment, or usual care treatment depending on the objective of the study These groups are then followed prospectively over time to observe the outcomes of interest that are hypothesized to be affected by the treatment or intervention. 19

20. Randomized Control Trials ADVANTAGES Best study type Greatest proof of causality Gold standard for other design Least bias Proves best treatment or procedure efficacy DISADVANTAGES Greatest expense Long duration 20

21. Other Experimental Studies Field trials: Field trials are another form of experimental study, used to study dietary factors and vaccines. In field trials the investigator makes the treatment available and then determines how well it works with careful follow up. Examples of field trials include studies of ascorbic acid in preventing the common cold. Community intervention trials: Community intervention trials are similar to field trials, but the treatment intervention is directed at a town or community such as fluoridation of drinking water to prevent dental caries . Quasi Experiments: when randomization is not feasible, the researcher can choose from a range of quasi-experimental designs that are non-randomized and often non-controlled. 21

22. Activity 22 Turning Research question to a well-built Research design Evidence based Medicine: PICO Q: In post-menopausal women, does HRT prevent osteoporosis?? P atient I ntervention C omparison O utcome Population Exposure Control Disease Postmenopausal HRT Placebo Osteoporosis

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24. Quality of Evidence 24

25. The New Drug Approval Process and Clinical Trial Design

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27. The New Drug Approval Process 1. Drug Discovery and Lead Compound Selection The process begins with identifying potential drug candidates through molecular screening, computer modeling, and biological testing. Scientists select a lead compound with promising therapeutic potential for further development. 2. Preclinical Testing (4+ years) This phase involves laboratory (in vitro) and animal (in vivo) studies to evaluate the safety and effectiveness of the drug before human trials. Biologic Activity Testing (in vivo): Determines how the drug interacts with biological systems. Chemical Synthesis and Scale-Up Testing: Ensures the drug can be produced consistently at a large scale. Formulation Development and Stability: Examines how the drug can be formulated for administration (tablet, injection, etc.) and ensures stability over time. Safety Testing in Animals: Identifies potential toxicity, side effects, and safe dosage levels . 27

28. The New Drug Approval Process IND (Investigational New Drug) Application: After successful preclinical testing, an IND application is submitted to the FDA (or relevant regulatory body) to seek approval for human trials. If concerns arise, the application may go into clinical hold for further revision. Upon IND approval, clinical trials can begin. 3. Clinical Testing (6+ years) Clinical trials involve human subjects and are conducted in three phases (Phase I, II, III trials ) 4 . FDA Review & Approval Process NDA Filing: If clinical trials are successful, the company submits an NDA for regulatory review. FDA Disapproval: If concerns are found, revisions may be required. FDA Conditional Approval: Allows limited marketing while more data is collected. FDA Full Approval: Grants permission for public sale and distribution. 📌 Market Entry & Post-Approval Surveillance: Once approved, the drug enters the market. Ongoing post-marketing surveillance (Phase IV trials) monitors long-term safety. 28

29. Phase I C linical Trials The first series of experiments performed in humans occurs during Phase I clinical testing. A small number of generally healthy volunteers (approximately 20-80 people) are exposed to the new drug product in closely monitored trials, primarily to assess the compound’s safety. For the investigation of drugs to treat life-threatening diseases, such as cancer or Acquired Immune Deficiency Syndrome (AIDS), patients afflicted with the disease may be enrolled . In Phase I trials, the starting dose is generally low, often 1/10 of the highest no-effect dose in the animal models . After the initial treatment is completed, additional subjects may be recruited and administered higher doses to determine the maximum dose tolerated without significant side effects. During this phase of testing, preliminary ADME data of the parent drug and all metabolites should be evaluated. Sufficient data regarding pharmacokinetic and pharmacological effects are also obtained to be used in designing future Phase II trials. 29

30. Phase II C linical Trials Phase II clinical testing shifts the focus of the trials from safety to efficacy. In comparison to Phase I trials, a larger number of people (100-300 patients) are enrolled in the trial and the majority of these participants suffer from the target illness. Side effects from the new drug product are also investigated. These clinical trials are closely monitored and well-controlled. Failure during Phase II testing is common, as the human body is more complex than the test tube. 30

31. Phase III C linical Trials Phase III clinical trials are the longest, most comprehensive trials regarding efficacy and safety of new compounds. Significantly larger numbers (1000-3000) of patients who are afflicted with the target illness are tested. Patients are often recruited, tested , and monitored by several major hospitals and clinics throughout the country. Phase III trials may also be conducted internationally . In addition to determining efficacy, these trials monitor adverse reactions. The new drug may be compared to existing therapeutic regimens ( ie , comparator products) or to placebo . The final market formulation for the drug product should be optimized prior to the start of these Phase III trials. Compounds that successfully complete Phase III testing have a 95 % chance of being approved by the FDA. 31

32. Phase IV C linical Trials Phase IV trials are post-approval clinical trials designed for one of several reasons. The FDA may mandate Phase IV testing in a specific patient population to further assess efficacy and side effects . Companies may also choose to conduct additional clinical tests to more fully understand how their product compares to other commercially available therapeutic regimens. Since duration of exposure is often limited during Phase III testing, Phase IV trials may be required to assess long-term safety of the drug. 32

33. Application of Statistical Procedures in Pharmacy and Medical Research

34. Application of Statistical Procedures in Pharmacy and Medical Research Statistics plays an important role in pharmacy and medical research by ensuring accuracy, reliability, and validity of research findings. It helps in designing studies, analyzing data, and drawing meaningful conclusions . Descriptive Statistics identify patterns leads to hypothesis generating Inferential Statistics distinguish true differences from random variation allows hypothesis testing 34

35. Statistical Procedures A. Descriptive Statistics Used to summarize and describe research data. 🔹 Measures of Central Tendency: Mean (Average value) Median (Middle value) Mode (Most frequently occurring value) 🔹 Measures of Dispersion: Range (Difference between max & min values) Standard Deviation (SD) (Spread of data) Variance (Degree of data variability) 📌 Example: In a clinical trial testing a new antihypertensive drug, the mean reduction in blood pressure is calculated to assess effectiveness. 35

36. Statistical Procedures B. Inferential Statistics Used to draw conclusions about a population based on sample data. 🔹 Hypothesis Testing: Null Hypothesis (H₀): No effect (e.g., Drug A don't lower the blood pressure). Alternative Hypothesis (H₁): Significant effect (e.g., Drug A lowers blood pressure). P-Value: Determines statistical significance (p < 0.05 is considered significant). 🔹 Confidence Intervals (CI): Estimates the range in which a true population parameter lies (e.g., "The drug reduces blood pressure by 10-15 mmHg with 95% confidence"). 📌 Example: A study compares two antihypertensive drugs. If p < 0.05 , the new drug is considered significantly more effective. 36

37. Statistical Procedures C. Experimental Design & Statistical Tests in Clinical Trials Used in clinical trials and drug development to compare treatment effects. 🔹 Common Statistical Tests: T-test: Compares means between two groups (e.g., Drug vs. Placebo). Chi-Square Test: Compares categorical data (e.g., Male vs. Female response to a drug). ANOVA (Analysis of Variance): Compares means across multiple groups (e.g., Different doses of a drug ). 37

38. Bio statistical Software Used in Pharmacy Research SPSS (Statistical Package for Social Sciences) R Programming SAS (Statistical Analysis System) GraphPad Prism 38

39. Causality A ssessment as well as the Sensitivity and Specificity tests in Pharmacy P ractice

40. Causality Assessment Causality assessment is the systematic evaluation of whether a drug is responsible for an adverse drug reaction (ADR). It is an important step in pharmacovigilance and drug safety monitoring, ensuring patient safety by identifying harmful drug effects . Methods for Causality Assessment Several tools and scales help assess how likely a drug caused an ADR. WHO-UMC (World Health Organization – Uppsala Monitoring Centre) System Naranjo Algorithm (Adverse Drug Reaction Probability Scale ) 40

41. WHO-UMC (World Health Organization – Uppsala Monitoring Centre) System Category Definition Certain Strong evidence that the drug caused the ADR, including reappearance after re-exposure ( rechallenge ). Probable The ADR is likely caused by the drug, but no rechallenge was done. Other causes are unlikely. Possible The ADR may be due to the drug, but other factors (e.g., patient’s condition, other medications) could contribute. Unlikely The ADR has a poor time relationship with the drug, and other causes are more probable. Conditional/Unclassified More data is needed before a decision can be made. Unassessable Insufficient or contradictory information prevents assessment. 41 This is a qualitative method that categorizes causality into six levels based on clinical evidence, time relationship, and alternative explanations.

42. Naranjo Algorithm (Adverse Drug Reaction Probability Scale) The Naranjo Scale is a quantitative method that assigns numerical scores based on a set of 10 questions related to drug exposure, time of reaction, alternative causes, and dechallenge / rechallenge effects . 42 Total Score Causality ≥ 9 Definite (Drug caused it for sure) 5-8 Probable (Likely caused by drug) 1-4 Possible (Maybe caused by drug) Doubtful (Probably NOT the drug’s fault)

43. Other Causality Assessment Methods 1 . Karch and Lasagna Criteria Classifies ADRs as definite, probable, possible, or doubtful based on temporal association and alternative causes . 2 . European A.B.O.N. Scale Categorizes ADRs as A (Very likely), B (Likely), O (Possible), N (Not related) . 3 . WHO Adverse Reaction Terminology (WHO-ART) Used in pharmacovigilance databases for global reporting. 43

44. Sensitivity and S pecificity Test Test Disease No Disease Positive Test True Positive (Sensitivity) False Positive Negative Test False Negative True Negative (Specificity) 44 Term Definition Sensitivity The ability of a test to correctly identify patients who have the disease (True Positives). Specificity The ability of a test to correctly identify disease-free individuals (True Negatives).

45. Sensitivity and S pecificity Test Sensitivity and specificity are key statistical measures used to evaluate diagnostic tests, screening methods, and drug efficacy in pharmacy practice. A highly sensitive test minimizes false negatives (FN), ensuring most cases are detected. A highly specific test minimizes false positives (FP), ensuring healthy individuals are not misclassified as sick. Mathematical Formulas Sensitivity (%) = TP / (TP + FN) × 100 Specificity (%) = TN / (TN + FP) × 100 45

46. Sensitivity and S pecificity Test Example Sensitivity = 90 / (90 + 10) × 100 = 90% Specificity = 90 / (90 + 10) × 100 = 90% High sensitivity (90%) ensures that infected individuals are detected. High specificity (90%) ensures non-infected individuals are correctly identified. Application in Pharmacy: Helps pharmacists interpret test results before recommending treatment. Guides selection of diagnostic tests in hospitals and community pharmacies . 46 Test Result Has COVID-19 (Yes) No COVID-19 (No) Positive (True Positive + False Positive) 90 10 Negative (False Negative + True Negative) 10 90 COVID-19 Rapid Antigen Test

47. References Remington, J. P. (2006). Remington: the science and practice of pharmacy (Vol. 1). Lippincott Williams & Wilkins. Winfield, A. J., Rees, J., & Smith, I. (Eds.). (2009). Pharmaceutical practice e-book. Elsevier health sciences. Mutnick , A. H., Souney , P. F., & Swanson, L. N. (Eds.). (2012).  Comprehensive pharmacy review for NAPLEX: practice exams, cases, and test prep . Lippincott Williams & Wilkins. 47