Non-interventional post-marketing studies: my experience in working with the pharmaceutical industry

Prof. Martin C. Michel
Institut für Pharmakologie
Johannes Gutenberg Universität
Obere Zahlbacher Str. 67
55101 Mainz
Germany
Mail: martin.michel@boehringer-ingelheim.com

Dear editor,
Anonymous recently described his/her experience in the drug industry with the design and use of non-interventional post-marketing surveillance (PMS) studies 1. While working in academia, I have collaborated with various pharmaceutical companies in the design, execution, analysis and publication of non-interventional PMS studies, and my experience differs considerably from that reported in the Journal. In the companies I worked with, including Astellas, Boehringer Ingelheim, Eli Lilly and Pfizer, there was a general consensus that non-interventional PMS studies primarily serve a scientific purpose. In contrast to the experience of Anonymous they typically had pre-defined scientific questions, were powered to answer these questions and had a pre-defined statistical analysis plan; in some cases they even had explicitly been recommended by the regulatory authorities. For example, they explored adverse event risks in high risk populations not represented in phase III registration studies in sufficient numbers 2-4 or used baseline data from such studies to get a better understanding of the underlying pathophysiology 5;6 or its assessment 7.

Non-interventional studies, when properly designed and executed are not scientifically inferior to randomized controlled trials (RCTs) but rather serve a different purpose. RCTs provide important information about the efficacy and safety of a drug relative to a reference treatment, often placebo, due to randomization, well-defined study populations and often blinding. However, the populations recruited for RCTs are not necessarily representative for those later receiving a given treatment in clinical practise and place patients and physicians into a somewhat arteficial setting, where expectations and perceptions on both sides are likely to differ from those during routine treatment. Thus, RCTs have high internal but limited external validity.

In contrast, non-interventional PMS studies often reflect a much broader spectrum of patients, are closer to the expectations in real life and, due to much lower per-patient trial costs often can recruit larger numbers of patients than would be possible in RCTs; their main disadvantage is the lack of a control group, but innovative designs can at least partly address this 8. This results in a lower internal validity but a greater external validity as compared to RCTs. Thus, due to the absence of a control group, they should not be abused for claims on the absolute efficacy of a given treatment. However, the often larg patient numbers can allow looking at relevant subpopulations and/or to apply multiple regression models for analysis of potentially related variables with adequate statistical power.

None of this is to claim that non-interventional PMS studies have not been abused in the past as marketing tools disguised by poor science. It is a shared responsibility of physician investigators, pharmaceutical companies and journal editors to ensure that only PMS studies with relevant scientific questions and methodology are performed and get published. If these criteria are applied, non-interventional PMS studies can make important contributions to medical knowledge.

Competing interest: In the past five years the author has received research support, consultancy and/or lecturer honoraria from Allergan, AltheRX, Astellas, Bayer, Boehringer Ingelheim, Eli Lilly and Pfizer. In 2011 the author became an employee of Boehringer Ingelheim. This letter does not necessarily reflect the views of his employer.

Reference List

(1) Anonymous. Post-marketing observational studies: my experience in the drug industry. Br Med J 2012; 344:e3990.
(2) Michel MC, Mehlburger L, Bressel H-U, Schumacher H, Schäfers RF, Goepel M. Tamsulosin treatment of 19,365 patients with lower urinary tract symptoms: does comorbidity alter tolerability? J Urol 1998; 160(3):784-791.
(3) Michel MC, Wetterauer U, Vogel M, de la Rosette JJMCH. Cardiovascular safety and overall tolerability of solifenacin in routine clinical use. Drug Safety 2008; 31(6):505-514.
(4) Michel MC, Schneider T, Krege S, Goepel M. Do gender or age affect the efficacy and safety of tolterodine? J Urol 2002; 168(3):1027-1031.
(5) Michel MC, Mehlburger L, Schumacher H, Bressel H-U, Goepel M. Effect of diabetes on lower urinary tract symptoms in patients with benign prostatic hyperplasia. J Urol 2000; 163(6):1725-1729.
(6) Michel MC, Heemann U, Schumacher H, Mehlburger L, Goepel M. Association of hypertension with symptoms of benign prostatic hyperplasia. J Urol 2004; 172(4):1390-1393.
(7) Michel MC, Oelke M, Goepel M, Beck E, Burkart M. Relationships among symptoms, bother, and treatment satisfaction in overactive bladder patients. Neurourol Urodyn 2007; 26(2):190-195.
(8) Manning M, Gotsch U, Minarzyk A, Quail D, Gross A, Pages I et al. How are women with SUI-symptoms treated with duloxetine in real life practice? - Prelimnary results from a large observational study in Germany. Int J Clin Pract 2009; 63(12):1724-1733.

Competing interests: In the past five years the author has received research support, consultancy and/or lecturer honoraria from Allergan, AltheRX, Astellas, Bayer, Boehringer Ingelheim, Eli Lilly and Pfizer. In 2011 the author became an employee of Boehringer Ingelheim. This letter does not necessarily reflect the views of his employer.