Abbreviations:CI (confidence interval), FDA (US Food and Drug Administration), IV (instrumental variable), RCT (randomized controlled trial)
- •Recognize the newest techniques in biomedical research.
- •Describe how these techniques can be utilized and their limitations.
- •Describe the potential impact of these techniques.
- •Pharmacoepidemiology research uses a variety of study designs and biostatistical techniques, including propensity scores, instrumental variables, and external adjustment, to reduce the confounding and systematic error associated with observational research.
- •Descriptive studies, including case reports, case series, cross-sectional, and ecologic studies are best used to identify potential safety signals and generate hypotheses.
- •Analytic study methods, including case-control studies, cohort studies, and clinical trials, are necessary to determine if causation can be inferred from an association and to confirm or refute a safety signal identified through descriptive studies.
Clinical Trials Have Significant Limitations for Detecting Drug Safety
Classification of Adverse Reactions to Medications
The Detection of Adverse Safety Events
Pharmacoepidemiology Study Designs
|Case report/case series||A description of a single patient or a series of patients|
|Cross-sectional study||The presence or absence of both exposure and disease are assessed at a single point in time|
|Ecological or secular trend study||A study comparing geographic and/or time trends of illness versus trends in risk factors|
|Case crossover study||A study comparing the pattern of exposure between an event time and a control time with each patient serving as his/her own control|
|Case-control study||A study that selects patients with the disease of interest (cases) and individuals without the disease of interest (controls). The case and control participants are evaluated for differences in prior exposure to various risk factors, yielding odds ratios as a measure of association.|
|Cohort study||A study that selects subjects on the basis of the presence (exposed population) or absence (control population) of exposure to a factor of interest. Researchers then follow subjects over time, looking for differences in a variety of outcomes, yielding relative risks as a measure of association.|
|Clinical trial||The investigator determines which patients receive an exposure and then follows the patients for the outcome.|
|Source of Error||Definition||Question To Be Answered|
|Confounding||An observed association, or lack of association, that is due to a mixing of effects between the exposure, the outcome, and a third confounding variable||Is there a third factor associated with both the treatment (exposure) and the outcome?|
|Confounding by indication||Systematic error that occurs when the disease itself, or symptoms of the disease, are risk factors for the outcome being studied.||Is the underlying disease being treated in the study a risk factor for the outcome?|
|Selection bias||Systematic error that arises from methods to select participants for a study that is related to the probability of developing the outcome of interest.||Were the two study groups selected into the study similar, with the exception of the exposure of interest?|
|Information bias||Systematic error that is associated with the measurement of the exposure or outcome.||Were data on the exposure and outcome measured/collected the same way in both groups?|
|Generalizability (external validity)||The applicability of the results to other populations||Do the results apply to the general population? Your patient population?|
|Type I (alpha error)||The probability of finding a significant association when the association is actually due to chance||Were the observed results due to chance alone?|
|Type II (beta error)||The probability of concluding that there is no difference when a real difference exists||What magnitude of effect was the study powered to detect?|
|Confidence interval||The range within which the true magnitude of the effect exists||Does the confidence interval include/exclude the relative risk that is important to detect?|
|Precision||The accuracy of the measured results, including the width of the 95% confidence interval||What was the range of results statistically consistent with the observed finding?|
|Time sequence||Does the time sequence between the exposure and the outcome make sense?|
|Biological plausibility||Is the relationship between the exposure and the outcome biologically plausible?|
|Dose-response||Is there a dose-response relationship?|
|Strength of study design||Clinical trials provide more strength for a causal association than observational studies (case-control or cohort studies), which in turn provide more strength for a causal association than descriptive studies.|
|Strength of association||How high is the point estimate? How wide is the confidence interval?|
|Consistency with previous research||Are there other studies with strong study designs showing an association?|
Advanced Biostatics Methods Applied to Pharmacoepidemiology
An Example of Pharmacoepidemiology in Dermatology: The Association Between Isotretinoin and Inflammatory Bowel Disease (IBD)
Multiple Choice Questions
- 1.A new drug has been studied in 3,000 patients before approval. The upper limit for the detection of rare adverse reactions in this safety database would be
- A.1 in 100.
- B.1 in 1,000.
- C.1 in 10,000.
- D.1 in 1,000,000.
- 2.Who can report a potential adverse drug reaction to the FDA?
- C.Drug manufacturers
- D.All of the above
- 3.Which of the following is an example of a type A adverse reaction?
- A.Agranulocytosis after starting diaminodiphenyl sulfone (dapsone)
- B.Cheilitis associated with isotretinoin
- C.Squamous cell carcinoma after psoralen plus UVA treatment
- D.Progressive multifocal leukoencephalopathy after efalizumab
- 4.Which of the following is true about spontaneous reporting of adverse drug events?
- A.Most adverse drug events that occur are reported to the FDA.
- B.Spontaneous reports can be used to calculate the incidence of an adverse event.
- C.Information generated from spontaneous reports should be subjected to further studies.
- D.Events are reported more commonly for older drugs.
- 5.Which of the following is an advantage of using propensity scores over traditional regression analysis?
- A.Propensity scores improve the efficiency of the analysis.
- B.Propensity scores can adjust for unmeasured confounding.
- C.Propensity scores randomize patients to a treatment arm.
- D.Propensity scores adjust for confounding by indication.
Conflict of Interest
- Quiz and brief explanation of correct answers
- Teaching Slides
- Isotretinoin use and the risk of inflammatory bowel disease: a population-based cohort study.J Invest Dermatol. 2013; 133: 907-912
- Era of faster FDA drug approval has also seen increased black-box warnings and market withdrawals.Health Aff. 2014; 33: 1453-1459
- Pharmacovigilance: verifying that drugs remain safe.in: Wolverton S.E. Comprehensive dermatologic drug therapy, 3rd ed. Elsevier, Philadelphia2013
- Trends in prescription drug use among adults in the United States from 1999-2012.JAMA. 2015; 314: 1818-1831
- Adverse drug reactions: current issues and strategies for prevention and management.Expert Opin Pharmacother. 2002; 3: 1289-1300
- Does exposure to isotretinoin increase the risk for the development of inflammatory bowel disease? A meta-analysis.Eur J Gastroenterol Hepatol. 2016; 28: 210-216
- Mini-sentinel and regulatory science—big data rendered fit and functional.New Engl J Med. 2014; 370: 2165-2167
- Sensitivity analysis and external adjustment for unmeasured confounders in epidemiologic database studies of therapeutics.Pharmacoepidemiol Drug Saf. 2006; 15: 291-303
- Cutaneous squamous-cell carcinoma in patients treated with PUVA.N Engl J Med. 1984; 310: 1156-1161
- Alleged isotretinoin-associated inflammatory bowel disease: disproportionate reporting by attorneys to the Food and Drug Administration Adverse Event Reporting System.J Am Acad Dermatol. 2013; 69: 393-398
- Pharmacoepidemiology.5th ed. Wiley-Blackwell, Hoboken, NJ2012
- CIOMS and ICH initiatives in pharmacovigilance and risk management: overview and implications.Drug Saf. 2004; 27: 509-517
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