Literature Evaluation

1. Literature Evaluation Types and Quality of Medical Literature Study Design

2. Types of Drug Resources- Tertiary • Tertiary Sources • Compendia (Facts and Comparisons, textbooks, Micromedex, review and meta-analysis articles) • Advantages: convenient, easy to use, quick access, compact information, general overviews • Disadvantages: incomplete, outdated, contains most human bias, lack of expertise and evidence.

3. Types of Resources: Secondary • Indexing and abstracting services (Medline) • Use: to locate primary drug literature resources • Advantages: easy access to primary resources • Disadvantage: cost, some only have indexing or abstracting available

4. Types of Resources: Primary • Articles in journals about original research or case reports of actual drug trials/studies. • Advantages: Provides significant detail of drug knowledge, research methodology, scientific results allowing the reader to evaluate the drug in the most non-biased and scientifically based way. • Most current, most unbiased, used for therapeutic decisions (actual research data).

5. Types of Literature Articles…Tertiary Resource • Review articles-- tertiary resource articles (not primary) • Purpose: to review a drug in a monograph form or in a literature search format where many articles are reviewed, clinical studies are looked at and conclusions are made that reflect the “current thinking” on a given subject or drug. • Advantages: Excellent beginning resource to locate information about a particular subject. Rapid access to large amount of information.

6. Types of Literature Articles….Tertiary Resource • Systematic Review • Summarizes scientific evidence—reviews multiple studies • One or more questions/hypotheses posed at start of review • Studies are collected to review, data is extracted and combined/compared; Or, if data cannot be combined, strength of evidence is assessed and used to evaluate results. • Conclusions are made based on results and presence or absence of supporting evidence.

7. Types of Literature Articles…Tertiary Resource • Meta-Analysis studies:tertiary resource information. • A quantitative or statistical method of combining the results of independent studies (usually drawn from published literature) and synthesizing summaries and conclusions, statistically, which may be used to evaluate therapeutic effectiveness, plan new studies, etc. • Used when measuring very small effects, to resolve conflict or inconclusive results among studies, or to evaluate objectives not posed at the beginning of the study. • Always has statistical evidence present. • Always a retrospective evaluation of collected data.

8. Types of Literature Articles in Medical Journals • Pharmacokinetic studies: • To estimate: • the drug’s pharmacokinetic parameters, such as volume of distribution, metabolism, elimination. • bioavailability or bioequivalence of drugs or dosage forms. • Drug interactions (food, drug, genetics) • Common in: phase I or II clinical trials • animal or human studies (small #s, healthy volunteers, not placebo controlled, not blinded, not randomized)

9. Types of Literature Articles in Medical Journals... • Pharmacodynamic Studies: • To evaluate drug concentration-effect relationships (if drug conc. Produce a therapeutic or toxic effect) • Can be animal or human studies (small #’s, healthy volunteers, not blinded, not randomized, not placebo controlled) • Common place: Pre-clinical and phase I trials. Often combined with pharmacokinetic studies.

10. Types of Literature Articles… • Pharmacoeconomic Studies • Studies identifying cost effectiveness for a given dosage regimen, disease state, or drug therapy • Provides additional information about the potential impact of a drug’s clinical use. • Example: A Study comparing the cost effectiveness of tricyclic antidepressants with the newer SSRI antidepressants in regards to actual pill costs and overall mental health care costs (hospitalizations, compliance with medication, longer term side effects, etc.) • Common place: phase IV trials

11. Types of Literature Articles... • Clinical Methodology Studies • Development of new methods compared to the current standards. • Example: A study to estimate the predictive performance of a new instrument, sensitivity and specificity of a diagnostic test or validation of a new drug dosing regimen. • Purpose: to look for more convenient, less expensive or less invasive means of making measurements.

12. Types of Literature Articles... • Pharmacoepidemiologic Studies • These studies evaluate the use and effects of drugs in large numbers of people. Used to assess drug use patterns and to document clinical efficacy and toxicity of drugs. • Have led to the discovery of uncommon, but serious side effects of drugs, leading to their withdrawal from the marketplace. • Most common type of design: cohort, case-control. • Common place: phase IV trials

13. Types of Literature Articles…. • Quality of Life Studies • performed to evaluate the functional effects, beneficial or adverse effects that a drug or treatment regimen may have on a patient and their quality of life. • Used to assess treatments that have minimal effects, to evaluate a drug in a disease state where few effective therapies exist, or to differentiate between drugs of the same class. • Most often in phase IV trials.

14. Editorial Board • Editorial boards are made up of people with expertise to critique the type of manuscript submitted for publication. • Editorial board members • Advise the editor about the suitability of submitted manuscripts • Assist the editor in setting journal policy

15. Peer Review • Experts in their field, asked to review, critique manuscripts before approval for publication. • Most journals do not identify peer reviewers for specific articles. • Peer reviewers may or may not be part of the editorial board.

16. Peer Review • How to tell if journal article has been peer reviewed: • 1. Look in “Guidelines for submitting manuscripts”. This will tell you how many copies of their manuscript they need to send in, and will often indicate if peer review is used. (If more than 2 copies, assume it is peer reviewed)

17. Peer Review…. • 2. Check either the bottom of the first page or the last page of the published study. Some journals will print the date they received a manuscript, the date it was revised and the date it was accepted for publication. The use of peer review will often mean that 3 months or more have lapsed from the time a manuscript is received by the journal to the time it is accepted for publication.

18. Peer Review…. • 3. If the manuscript has been revised, it usually means it has been peer reviewed and the author has been asked to make changes. • 4. Some journals will put a special symbol in the side margins or at the end of those articles that have been through the peer review process.

19. Advertising in Journals • The amount of advertising (ads for specific drugs, books, equipment, etc) varies from journal to journal, and ranges from none to the majority of the contents. • Advertising does not in itself affect the quality of a journal, but it does lower the cost of the journal for its readership.

20. Controlled Circulation • Several journals are distributed free of charge, with their cost entirely absorbed by advertisers. • These journals focus on a specific target audience (community practitioners, retail RPh, etc) and distribution is targeted to these individuals. This method of targeting is called “controlled circulation”. • Controlled circulation journals usually do not contain comprehensive research or clinical studies. • They can provide topic overviews of interest as review articles.

21. Citations • Citations (references) indicate the author has researched the subject and has used previous published work as a guide to this research. • Caution- Sometimes an author will cite his own work from a previously written article on the same/similar work-- can create bias and lower the quality of the reference

22. Review of Clinical Trial Phases • Phase I: to identify preferred route, safe dosage range, toxicity, pharmacokinetics. Uses healthy volunteers w/ no pre-existing conditions. Uses low dosages. • Phase II: to evaluate efficacy in subjects with proposed disease state; identify group most likely to benefit from drug.

23. Review of Drug Trial Phases • Phase III: Compare to current therapy, multicenter studies, serve as basis for NDA, large numbers of patients tested. • Phase IV: Post marketing surveillance studies, to look for side effects, new indications, new dosages, long term effects, drug interactions in defined populations.

24. Drug Study Design

25. Purpose of a Study Design • To answer a research question. • The research design determines what can be concluded from a particular study and the amount of inference required to interpret the data. • Research design influences the selection of the statistical procedures used to analyze and interpret results.

26. Research Design • Organized around three general concepts: • Description • Analysis • Evaluation • 2 basic types of medical research studies: • Observational • Experimental

27. Hierarchy of Research Design • Lowest levels of evidence: • Descriptive • Cross Sectional • Case-Control • Higher levels of evidence: • Cohort • Highest levels of evidence: • Experimental (randomized controlled study)

28. Types of Medical Studies... • Observational • prospective (happening in present and future) • retrospective (looking backwards for data) • observing only, no direct intervention • Experimental • always prospective • investigators of study have direct intervention

29. Observational Designs • Descriptive (Case-Series, Case Report) Study • describes situation in group of patients, or interesting or unique phenomena. • No comparison or control patient groups are used. • Example: 15 patients are described in whom resolution of herpes zoster occurred following the initiation of Tagamet therapy for peptic ulcer. All pts. began therapy with Tagamet 300 mg QID for peptic ulcer disease during the time they were having acute episodes of herpes zoster. The zoster resolved in 3 days

30. Descriptive (Case Series, Case Report) • Advantages • Relatively easy and inexpensive to perform • Provides preliminary information that could prove valuable upon further study- raises questions that may prompt more studies • Disadvantages • Patients might not be representative of others with the specific condition • Information provided is subject to many potential biases.

31. Observational Design- Cross Sectional Study • Sometimes called Prevalence or Survey Study. • Used to determine the existence of specific conditions or characteristics at one given point in time. It identifies a sample population and makes an assessment of outcome all at the same time. • No controls used

32. Cross-Sectional Study • Example: A study selects patients which have had an adverse drug reaction to a glaucoma medicine. The study looks for risk factors at the time the study patients were selected. • Example: Study to determine whether serum creatinine increases with age. SCr levels were measured in 400 healthy subjects, between 18-70 y.o. The relationship between age and serum creatinine were then analyzed. The analysis showed the strength of the relationship or association and the direction of the relationship or association.

33. Cross-Sectional Study Design • Leads to the “Chicken and the Egg” dilemma of which came first. Does the patient have the ADR because of the risk factor or is the risk factor a manifestation of the disease, ADR, or a confounding factor?

34. Cross-Sectional Study Design • Advantages • Less time consuming to perform • Least expensive to perform • Easy to complete (sometimes survey form) • Appropriate for evaluating the current status of a condition or characteristic. • Useful for measuring prevalence, association, and estimating risk with odds ratios.

35. Cross Sectional Study Design • Disadvantages: • Bias may be introduced if the measured outcome depends on chart review or recall information (selection bias, subject bias, investigator bias) • Transient effects: If the condition being monitored can change over time, the results can be inaccurate or misleading. • Does not establish causation • No control group

36. Observational Design- Case Control Study • Case-Control Study • Used to determine the possible factorsinfluencing (risks), or the causes of, an observed event or outcome. Since one is looking back in time to identify the factors or causes of the observed event or outcome, the design is always retrospective. • The “cases” are the patients who have the observed event or outcome. • The “controls” are similar to the cases, except that they do NOT have the observed event or outcome. The factors that are different between the cases and controls are then examined in terms of the ability to influence the event or outcome. • Always 2 groups of patients: one group with outcome, one group without outcome.

37. Case-Control Study • Study Example: • A study was conducted to evaluate the risk of leukemia resulting from the use of cancer chemotherapy to treat breast cancer. The patient files of 90 women with breast cancer diagnosed from 1973 to 1985 who developed leukemia were examined. Two to 3 additional patients with breast cancer but without leukemia were matched to each of the other 90 patients and examined. It was found that leukemia was uncommon in patients with breast cancer, although the risk of developing it was significantly enhanced by the use of regional radiation.

38. Case-Control Study • Always retrospective. • Control group used (without outcome) • Reports odds ratios and risk ratios • Outcome is known- you are looking for factors influencing the development of the outcome. • Measures risks. • Sometimes called Trohoc studies

39. Case-Control Study • Advantages • Relatively quick to perform • Generally inexpensive • Appropriate for studying rare diseases or conditions which take several years to develop.

40. Case-Control Study • Disadvantages • Dependent upon accuracy and completeness of existing records of past events. • Cannot evaluate cause and effect of measure incidence-- only prevalence and association. • Easily biased by the retrospective nature. • Berkson’s Bias: Difficult to obtain “controls” which are truly comparable to the “cases” • Protopathic Bias: A disease leads to exposure of risk factor rather than visa versa.

41. Berkson’s Bias • The more similar the case and control groups are to each other, the more likely a difference found between the groups will be due to the variable being assessed instead of random variation. • Example: A study who uses subjects drawn from hospitalized populations whose exposure to the risk factor may differ from a population in the community.

42. Protopathic Bias • A disease leads to exposure of the risk factor rather than the exposure of the risk factor leading to the disease. • Example: Vaginal bleeding may be an early sign of uterine cancer. But vaginal bleeding leads to the use of progesterone. A study may say that progesterone caused cancer but, maybe the cancer preceded the progesterone use.

43. Terminology • Prevalence rate: The proportion of existing cases of a medical condition in the population at risk at a specified point in time. For example, the prevalence of hospitalized-acquired pneumonia is the number of cases divided by the total number of patients hospitalized at a particular point in time.

44. Terminology • Incidence Rate: The ratio of the number of new cases of a condition to the total number of persons in the population at risk for the condition during a specified period. For example, the incidence of a condition developing may be reported as the percentage per person per year.

45. Terminology • Odds Ratio: A relative measure of disease occurrence that provides an estimate of the relative risk. It is defined as the frequency with which the event occurs divided by the frequency with which it does not occur and is usually calculated for case-control studies where the incidence is not known.

46. Observational Design- Cohort Studies • Longitudinal study and observational in nature. • Example: study looking for drug-drug interactions. • Cohort: group of patients who have not yet experienced the outcome under study. • Cohort Study: characteristics of the cohort are recorded over time as the investigator observes them waiting for the outcome to occur. • Does use a control group

47. Cohort Study • Prospective Cohort: follows or observes patients both with and without certain characteristics/features over time period to determine what outcomes will be. • Retrospective (historical) Cohort: Patients are followed both with and without certain features but all information is collected from the past (records, charts, billing claims etc)

48. Cohort Study • Advantages of Cohort Study • Usually a clear relationship between risk factors and the outcomes can be determined. • Allows for uniform data collection and avoids recall bias (prospective cohort). • Useful for measuring incidence, relative risk, association and causation • Uses a control group -ranks higher for “levels of evidence” in evidence base medicine)

49. Cohort Study • Disadvantages of Cohort Study • Exact causes of an outcome cannot be definitively proven since only observations are being made (no intervention) • Expensive if patients are followed over long period of time • Drop out rate can be higher if study is over long period of time.

50. Hawthorne Effect • Subjects change their behavior while being observed (if they know they are being watched, they will perform differently) • This can increase compliance and increase side effects.