Dose optimization in drug development: role of phase IV trials

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Abstract

Intense competitive pressure may require short development times and can result in approval of safe and effective dose regimens that are suboptimal. 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 patient compliance. Improved efficacy: The efficacy of HIV-protease inhibitors (e.g., saquinavir) has been improved by formulations or combinations exhibiting higher bioavailabilities. For lisinopril, a large phase IV trial showed that a dose much higher than that widely used was necessary to reduce mortality in patients with congestive heart failure. Reduced risk: Captopril, the first angiotensin-converting enzyme (ACE) inhibitor to reach the market was initially marketed at too high a dose. A reduction in dose markedly reduced the risk of nephrotoxicity while maintaining anti-hypertensive efficacy. New indications: There are numerous examples such as the expansion of indications of beta-adrenergic blockers, calcium antagonists, and ACE inhibitors. New dose regimens: With saquinavir, it was possible with phase IV studies to demonstrate that efficacy (in terms of viral load) achieved with a three-times-daily regimen was maintained by a twice-a-day regimen. With nifedipine, it was shown that with slow infusion, there was effective blood pressure lowering and no compensatory tachycardia, whereas rapid infusion led to tachycardia with no blood pressure lowering. This allowed the development of a highly successful slow-release formulation. 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.

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.

Section snippets

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.

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