The full public health benefit of new medicines is often only partially documented in the literature because of a lack of appropriate information. Much of this information is compiled after the drug is registered and has been available on the market for a large number of years. Such post-registration studies describe parameters of real-life clinical practice such as the treated population, conditions of treatment initiation, treatment duration, adherence, associated benefits/risks as well as the impact on treatment strategies, healthcare procedures and on public health and importantly morbidity and mortality (Citation1) assessed in many ways. In France, it is currently carried out by the National Health Authority, by assigning a level of improvement in actual benefit (IAB) (Citation2). IAB is based on two parameters – efficacy and safety of the product – in a defined target population, compared with one or more other drugs with similar indications, or within a similar therapeutic strategy.
What role do post-registration studies play in the long-term risk and benefit assessment of drugs, and what conditions and methodologies could be used for such assessment?
In order to improve our knowledge on appropriate benefits and relevant risks, a number of questions may be raised, such as e.g. what study procedures to follow in monitoring studies carried out after a drug has been authorized. How can health authorities establish relevant guidelines and a methodological basis for specifications; which purposes should be addressed; and which methodologies are relevant in terms of design and execution?
Epidemiological observational monitoring of antihypertensive drugs are now well established, and applied to assessment of non-cardiovascular outcomes, extended therapeutic effects adverse events profiles, therapeutic benefits in special populations, relative added value with respect to available treatments as well as public health benefit in a regional and global perspective ().
Table I. Aspects on purpose and design of clinical studies for post-registration evaluation of antihypertensive drugs.
The current Blood Pressure Drug Therapeutic Issue includes three studies, which have evaluated the extended efficacy and safety of antihypertensive treatment regimens in multi-center open settings (Citation3,Citation4,Citation5). The paper by Liou and coworkers (Citation3) evaluated a large cohort of Taiwanese hypertensive patients treated with valsartan alone or in combination with other antihypertensive drugs. In this setting, they report that valsartan monotherapy was well tolerated, and that higher doses as well as combination therapy provided added benefits to the lower dose range and monotherapy, respectively.
The combination of metoprolol and amlodipine in two dose levels was evaluated by Delvi et al. (Citation4) in an Indian cohort of patients with mild to moderate hypertension. Responder and control rates were high with both fixed dose combinations and provided clinically meaningful reductions in blood pressure compared with respective monotherapies. The issue of potential benefits and risks with early versus late uptitration of antihypertensive treatment was addressed in the paper by Girerd and co-workers (Citation5). In patients receiving monotherapy, an uptitration was made either within two or six weeks. Although control rates with the two titration regimens were largely similar, serious adverse events were more frequent in the early as compared to the late uptitration groups. Based on these findings the authors indicate that in absence of clear proven benefits by a rapid blood pressure lowering effect in patients already receiving monotherapy, the present data may argue that a slower drug dose titration therapy seems to be reasonable in such patient groups. There is a growing realization of the importance of assessing the risk/benefit ratio for antihypertensive drugs after registration. One potential problem in doing this is that there is a range of methods to assess and monitor putative benefits as well as a potential risks. Such post-registration evaluations may be based on several sources of data, where the primary objective was not primarily the monitoring of risk. However, studies based on observational or PROBE methods (Citation6) can provide us with valuable information on how the drug is being used and to what extent there are benefits in terms of reduced morbidity and mortality in the clinical setting (Citation7,Citation8,Citation9).
References
- Molimard M, Bamberger M, Vray M. Value of post-registration studies for reimbursement renewal. Therapie. 2009; 64:203–213.
- Le Jeunne C, Woronoff-Lemsi MC, David N, de Sahb R. Relative added value: What are the tools to evaluate it? Therapie. 2008;63:107–111.
- Liou C-W, Yeh T-C, Chen I-C, Huang C-H, Hung Y-J, Hsu K-L, . Efficacy and safety of valseartan in hypertensive Taiwanese patients: Post-marketing surveillence study. Blood Press. 2011; 20 Suppl 2:13–21.
- Devi P, Xavier D, Sigamani A, Pandey S, Thomas T, Murthy S, . Effect of fixed dose combinations of metoprolol and amlodipine in hypertension: MARS – A randomized controlled trial. Blood Press. 2011;20 Suppl 2:5–12.
- Girerd X, Rosenbaum D, Aoun J on behalf of ACTUAL Study Investigators. Efficacy and safety of early versus late titration of fixed-dose irbesartan/hydrochlorothiazide: ACTUAL study. Blood Press. 2011;20 Suppl 2:22–29.
- Hansson L, Hedner T, Dahlöf B. Prospective Randomized Open Blinded End-point (PROBE) study. A novel design for intervention trials. Blood Press. 1992;1:113–119.
- Wieringa NF, Rein Vos R, Van Der Werf GT, Van Der Veen WJ, De Graeff PA. Co-morbidity of ‘clinical trial’ versus ‘real-world’ patients using cardiovascular drugs. Pharmacoepidemiol Drug Safety. 2000;9:569–579.
- Parati G, Staessen JA. Hypertension drug trials based on ambulatory blood pressure monitoring: When is a double-blind controlled design needed? J Hypertens. 2003;21:1237–1239.
- Massol J, Puech A, Boissel JP; Participants in Round Table No 7, Giens XXII. How to anticipate the assessment of the public health benefit of new medicines? Therapie. 2007; 62:427–435.