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ENCePP Guide on Methodological Standards in Pharmacoepidemiology


4.1. Primary data collection


The methodological aspects of primary data collection studies are well covered in the textbooks and guidelines referred to in the Introduction chapter. Annex 1 of Module VIII of the Good pharmacovigilance practice provides examples of different study designs based on prospective primary data collection such as cross-sectional study, prospective cohort study, active surveillance. Surveys and randomised controlled trials are presented below as examples of primary data collection.


Studies using hospital or community-based primary data collection have allowed the evaluation of drug-disease associations for rare complex conditions that require very large source populations and in-depth case assessment by clinical experts. Classic examples are Appetite-Suppressant Drugs and the Risk of Primary Pulmonary Hypertension (N Engl J Med 1996;335:609-16), The design of a study of the drug etiology of agranulocytosis and aplastic anemia (Eur J Clin Pharmacol 1983;24:833-6) and Medication Use and the Risk of Stevens–Johnson Syndrome or Toxic Epidermal Necrolysis (N Engl J Med 1995;333:1600-8). For some conditions, case-control surveillance networks have been developed and used for selected studies and for signal generation and clarification, e.g. Signal generation and clarification: use of case-control data (Pharmacoepidemiol Drug Saf 2001;10:197-203).


4.1.1. Surveys


A survey is a data collection tool used to gather information about individuals. Surveys are commonly used to collect self-reported data, either on factual information about individuals, or their opinions. They generally have a cross-sectional design and represent a form primary data collection conducted through questionnaires administered by web, phone or paper.


Although used for a long time in other areas as social science or marketing, surveys are nowadays also increasingly used in pharmacoepidemiology, especially in the areas of epidemiology and evaluation of risk minimisation measure (RMM) effectiveness (See chapter 5.9).


Questionnaires used in surveys should be validated based on accepted measures including construct, criterion and content validity, inter-rater and test-retest reliability, sensitivity and responsiveness.

Recommendations with regards to data collection, which medium to use, how to recruit a representative sample and how to formulate the questions in a non-directive way to avoid information bias, are described in the following textbooks: Survey Sampling (L. Kish, Wiley, 1995) and Survey Methodology (R.M. Groves, F.J. Fowler, M.P. Couper et al., 2nd Edition, Wiley 2009).


Although primarily focused on quality of life research, the book Quality of Life: the assessment, analysis and interpretation of patient-related outcomes (P.M. Fayers, D. Machin, 2nd Edition, Wiley, 2007) offers a comprehensive review of the theory and practice of developing, testing and analysing questionnaires in different settings. Health Measurement Scales: a practical guide to their development and use (D. L. Streiner, G. R. Norman, 4th Edition, Oxford University Press, 2008) is a very helpful guide to those involved in measuring subjective states and learning style in patients and healthcare providers.


Representativeness is an important element for surveys; the included sample should be representative of the target population and must be defined with regards to the research question. For example, if the objective of the survey is to evaluate whether the RMM are distributed among the right target population, the lists which are used for the distribution of the RMM material cannot be used as the source population for sampling.


The response rate is also an important metric of survey and it should be reported in a standardised way for each survey so that the comparison among different surveys is possible. Standard Definitions. Final Dispositions of Case Codes and Outcome Rates for Surveys of the American Association for Public Opinion Research provides standard definitions which can be adapted to pharmacoepidemiological surveys. The overall response rate of participation remains low in telephone surveys (J.M. Lepkowski, N.C. Tucker, J.M Bricket al., Ed. Advances in telephone survey methodology Wiley 2007, Part V) and is important to counteract since it leads to lack of power and reduced representativeness. A way to mitigate the low response rate is to include the use of short or personalised questionnaires approved by professional associations.


4.1.2. Randomised clinical trials


Randomised clinical trials is an experimental design that involves primary data collection. There are numerous textbooks and publications on methodological and operational aspects of clinical trials and they are not covered here. An essential guideline on clinical trials is the European Medicines Agency (EMA) Guideline for good clinical practice E6(R2), which specifies obligations for the conduct of clinical trials to ensure that the data generated in the trial are valid. From a legal perspective, the Volume 10 of the Rules Governing Medicinal Products in the European Union contains all guidance and legislation relevant for conduct of clinical trials. A number of documents are under revision. 


The way clinical trials are conducted in the European Union (EU) will undergo a major change when the Clinical Trial Regulation (Regulation (EU) No 536/2014) will come into application and will replace the existing directive.


Hybrid data collection as used in pragmatic trials, large simple trials and randomised database studies are described in Chapter 5.6.



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