Dose optimization in drug development: role of phase IV trials
Introduction
In spite of the rigor and competitiveness with which drug development is currently performed, pressure on timelines and resources require focussed and streamlined approaches looking at priorities. At the time of approval and launch of a product, there may often be many unanswered questions. Furthermore, with day-to-day use of a new product in practice, the situation is very different compared to the controlled environment of clinical trials. The post-approval period (phase IV) is consequently a very important time for increasing the knowledge base with respect to new drugs. This is the time when issues not apparent in the clinical trial environment might appear, and questions not addressed during a frantically paced drug development program can be investigated. Key sources of useful information during this period are post-marketing surveillance, spontaneous case reports, and phase IV studies in healthy volunteers and patients. This review will focus on the contribution that formal clinical trials can bring in the post-registration period.
There is a spectrum of consequences that may result from intense competitive pressure and short development times (Fig. 1). Although a safe and effective dose regimen may be approved, at one extreme, a “one dose fits all” approach with emphasis on efficacy can result in pivotal trials with a single high dose (e.g., the maximum tolerated dose) leading to an approved label which does not allow individualization of therapy. This could result in an incidence of adverse events which is higher than necessary. At the other extreme, physicochemical properties of a compound or practical restraints during development may prevent the full dose–response relationship from being adequately characterized resulting in an approved dose that is too low for optimal efficacy.
Well-designed phase IV studies can lead to identification of doses and dose regimens that may improve efficacy and/or reduce risks (resulting in an improved risk/benefit ratio). Furthermore, new indications can be explored and new dose regimens and formulations may be developed to optimize therapy and improve patient compliance.
There are many historical examples of drug dosages and regimens changing as experience with a drug accumulates. Initial use of digitalis involved escalating the dose until toxicity occurred. This was then adapted to rational dose selection based on factors such as renal function and electrolyte status. A further example is the realization that low doses of thiazide diuretics have a minimal risk of electrolyte disturbances and adverse effects on glucose metabolism and lipid profiles while maintaining anti-hypertensive efficacy.
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Discussion
In this section, I will review a number of examples from diverse therapeutic areas to illustrate how during phase IV, efficacy was improved or safety risk reduced (improved risk benefit), new indications emerged and improved dose regimens emerged. As all these factors impact on each other, many of the examples could fit into more than one of these categories. For a particular example, however, I have focussed on a characteristic appropriate to the heading.
Improved efficacy: In the human
Conclusions
It is clear, from the perspective of a drug developer, that successful registration of a new medicine is not the end of the drug development process but a gateway to intelligent life cycle management aimed at optimizing patient benefit and assuring commercial viability.
References (12)
- et al.
Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine
N. Engl. J. Med.
(1996) - et al.
Relationship between exposure to saquinavir monotherapy and antiviral response in HIV-positive patients
Clin. Pharmacokinet.
(1999) - et al.
Pharmacokinetic drug interaction with saquinavir soft gelatin capsule
- et al.
Safety and pharmacokinetics of once-daily regimens of soft-gel capsule saquinavir plus minidose ritonavir in human immunodeficiency virus-negative adults
Antimicrob. Agents Chemother.
(2000) - et al.
High dose saquinavir plus ritonavir: long term efficacy in HIV-positive protease inhibitor-experienced patients and predictors of virologic response
J. Acquired Immune Defic. Syndr.
(1999) - et al.
Adverse events of angiotensin converting enzyme (ACE) inhibitors
Drug Saf.
(1992)