Post-marketing studies of new insulins: sales or science?BMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e3974 (Published 12 June 2012) Cite this as: BMJ 2012;344:e3974
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Promotional use of post-marketing observational studies (also called non-interventional post-authorisation studies) is a serious concern that has contributed to discredit observational studies in the past 1. Recent post marketing studies of new insulins have been pointed to be more marketing than science 2. Some of these studies were carried out in low-income countries, but also in some high-income countries of Europe 3. It is under discussion the way these studies can still be used as marketing tools, and if the regulation is tight enough to ensure a proper balance between the commercial and clinical functions 4,5,6,7.
Regulation of non-interventional studies by national authorities is not standardized in Europe as opposite to what occurs with the well-regulated clinical trials. Although the European Clinical Trial Directive (2001/20/EC) 8 was not intended to regulate observational studies, the definition of non-interventional study was included. In this respect, non-interventional study is defined as "a study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data".
This definition, not only based in methodological criteria, but also in finalistic regulatory purposes, leads to unfortunate classifications.
Restricting observational studies to these investigating medicines used in accordance with the terms of their marketing authorisation makes some purely observational studies to be classified as clinical trials. An extreme case is represented by drug utilization studies that, if the definition is strictly interpreted, will be considered clinical trials, since all uses, including uses outside the terms of the marketing authorisation, will be recorded.
Clinical practices are not the same among countries, not even within the same country, and change over time. Consequently to determine precisely when a study is based on “the current clinical practice” is challenging, especially in multinational studies.
Many studies are usually driven to the clinical trials category because they use “additional diagnostic or monitoring procedures”, even if these procedures do not carry additional risk for the participating subjects. An extreme example is a case-control study that requires a diagnostic test (e.g. electrocardiogram) to confirm the cases.
The problems raised by the application of the current definition on non-interventional studies have been recently discussed 9. In addition, the European Commission has recently posted a document on the revision of clinical trials Directive under public consultation, in which there were some questions on the definition of non-interventional studies 10. A total of 134 responses from investigators, pharmaceutical companies, patient associations, scientific societies and assurance companies, have been received; 85 of them gave an opinion on the current non-interventional study definition. From them, 45 (53%) responses showed disagreement with the current non-interventional study definition or claimed for a change. This is a clear sign of the discomfort the current definition creates.
The lack of specific regulation on non-interventional safety studies across Europe may explain the current ambiguous definition of non-interventional trial, in an attempt to drive a number of observational studies to the clinical trials category, with a more consistent legislative framework.
Unlike randomized clinical trials that are rigidly designed to address very specific questions, observational studies exploit a wide range of methods and data sources 11. Thus, the definition of observational study ideally should have a methodological basis and therefore be limited to “A study where the assignment of the patient to a particular therapeutic strategy (exposure) is not decided in advance by a trial protocol and the prescription of the medicine is clearly separated from the decision to include the patient in the study”.
Then, regulators may impose the necessary requirements to observational studies; always proportionate according to their design, to warrant that the protocol enables to reach the objectives, the compliance with ethical postulates in clinical research 12 and to avoid their promotional use.
The first national regulation on observational studies was first published in 1990 to eradicate promotional studies in Spain. Since 2002, an Ethics Committee assess every non-interventional post-authorization study, and those with prospective follow-up design are further evaluated and authorized by the competent authority. A significant increase in the ethical and methodological quality of the studies was observed with the implementation of these requirements 13,14 and a number of non-interventional post-authorization studies with merely promotional objectives have been avoided (Figure 1).
The new European legislation on pharmacovigilance 15 is a step forward in the harmonization of the regulation of the post-authorisation safety studies and states that “the studies shall not be performed where the act of conducting the study promotes the use of a medicinal product”. Protocols of studies that competent authorities require to marketing authorisation holders will be overviewed by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency 15. The protocol as reviewed by the PRAC will be implemented as such in all European sites where the study is to be performed, and this will certainly facilitate the performance of these studies.
Post-marketing studies can make important contributions to medical knowledge, however a workable methodological definition is still needed. Otherwise, the progress to be achieved with the new European legislative framework will not be possible. Regulation of post-marketing studies by authorities should warrant that they are legitimate and not simply a pretext to generate prescriptions of a drug. Specific regulation at national level has showed to be effective avoiding promotional studies.
1 Kessler DA, Rose JL, Temple RJ, Schapiro R, Griffin JP. Therapuetic-class wars-drug promotion in a competitive marketplace. N Eng J Med 1994; 331:1350-3
2 Gale EAM. Post-marketing studies of new insulins: sales or science? BMJ 2012; 344:e3974. (12 June)
3 Yudkin JS. Post-marketing observational trials and catastrophic health expenditure. BMJ 2012; 344: e3987. (12 June)
4 Anonymous. Post-marketing observational studies: my experience in the drug industry. BMJ 2012; 344: e3990. (12 June)
5 Godlee F. More marketing than science. BMJ 2012; 344:e4269. (21 June)
6 Roehr B. FDA should tighten post-marketing surveillance of prescription drugs, says Institute of Medicine. BMJ 2012; 344: e3104 (1 May)
7 Michel MC. Post-marketing studies can make important contributions to medical knowledge. BMJ 2012; 345: e4740. (16 July)
8 Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.
9 European Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). Considerations on the definition of non-interventional trials under the current legislative framework (“clinical trials directive”2001/20/EC). http://www.encepp.eu/publications/documents/ENCePPinterpretationofnonint...
10 EC Public consultation. Available online on http://ec.europa.eu/health/human-use/clinical-trials/developments/ct_pub....
11 C J Mann. Observational research methods. Research design II: cohort, cross sectional, and case-control studies. Emerg Med J. 2003;20(1):54-60.
12 Council for International Organizations of Medical Sciences (CIOMS 2009): International Ethical Guidelines for Epidemiological Studies. Geneva, CIOMS.
13 Zafrilla BP, García del Pozo J, Ros AA, de Abajo FJ. Quality of observational post-authorization studies registered in Spain before their regulation. Med Clin (Barc). 2006 29;126(16):607-10.
14 De la Fuente C, Macías D, Vargas Castrillón E, de Abajo FJ. Non-interventional post-authorisation studies in Spain: impact of the 2002 regulation. Med Clin (Barc). 2010 18;135(9):423-7.
15 Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use.
We want to thank Professor Stephan Evans from the London School of Hygiene & Tropical Medicine, for invaluable advice and criticism.
Competing interests: No competing interests