Early-phase clinical trials are an important part of the drug development process. Although traditional scientific goals such as defining doses and toxicity, and assessing pharmacokinetic profiles will remain vital, other parameters like trial endpoints and design are gaining prominence.

Randomised, single assignments dominated product development design in the past, but do the early-stage clinical trials initiated today follow the same pattern? With reduced timelines, more detailed patient selection criteria, the progressively increasing complexity of the inferences drawn and the dismantling of redundant drug development models, the clinical landscape is brimming with interactive technologies, adaptive designs, and more intuitive ways to recruit and monitor patients.

According to GlobalData, early-phase clinical trials increased by 79% between 1996 and 2012. However, as a percentage of total clinical trials, the figure has remained almost the same. This is due to the increasing number of products that are dropped in the early stages of development.

The number of clinical trials ongoing in oncology is more than twice the number of trials in any other therapeutic segment. Yet, despite being the most commonly tested therapies, oncology drugs have the worst approval rates. Only 5% of agents with anti-cancer activity in preclinical development are licensed (Hutchison et al., 2011).

Early-phase trials were often viewed to be merely scientific, with less therapeutic assessment, because of the low response rates among an unselected patient population. More recently, early-phase clinical trials using targeted therapies have been modified, with study designs now incorporating endpoints like response rates and quality of life (QOL).

According to an article published in Journal of Clinical Oncology (Vol 18, No 2 (January) 2000: pp 421-428), QOL is reported to affect the expectation of benefit from experimental therapy and, ultimately, impact treatment choice. Therefore, including QOL as an endpoint in cancer subjects can have a positive effect on patient expectation and may lead to improved strategies in conducting early-phase clinical trials.

Recent early-stage clinical trials have tailor-made protocols and endpoints suitable to the requirement of the indication in question. Of course, there still are vanilla dose comparison/escalation studies, but more and more studies are now aiming at forecasting the safety and efficacy futures of the drug.

The endpoints are not the only factor being rethought; complete study designs are no longer fixed or pre-set, as the design of a clinical trial is key to enhancing the reliability and validity of the study.

"Early-phase clinical trial designs now incorporate end points like response rates and quality of life (QOL)."

Study design trends have shifted from non-randomised, single group assignments to randomised, parallel group assignments. Product investigation teams are acknowledging the important impact designing placebo-controlled trials can have in the early phases of drug development.

Recent recruitment strategies have made globalisation not only a trend in early-stage clinical trials, but also a pre-requisite in some cases, to find the right target population and improve recruitment.

A constant increase in the number of early-stage clinical trials conducted in BRIC and EU5 nations has been observed. The number of clinical trials has increased by almost 68 times in the BRIC nations and 15 times in the EU5 nations, compared with the mere 2.5 times increase in the early-stage clinical trials initiated in the US from 1996 to 2011.

In spite of the overwhelming rise in the number of early-stage clinical trials in the BRIC nations, the US continues to occupy a 20% of the overall share of the early-phase market.

Changing paradigm in early stage clinical trials

According to GlobalData, several novel early-phase studies have changed the cancer therapeutics landscape and it has been observed that early biomarker identification can substantially increase therapeutic benefit and shorten the drug development timeline.

Early biomarker identification and selecting patients based on their personal molecular profiles are the cornerstones of a critical paradigm shift needed to improve outcomes for patients with advanced, refractory cancers. Therefore, the goals of properly performed phase I trials should clearly be scientific as well as therapeutic.

There has been a shift in study design protocol in early-phase clinical trials. Previously, fundamental factors such as maximum tolerated doses were evaluated; now, response rates and other critical parameters are taken into account.

Generating sufficient information about drugs’ pharmacokinetics and pharmacological effects in early-phase trials is critical to design well controlled, scientifically valid, phase II studies. Phase I clinical trial outcomes today are lucid enough to aid pharmaceutical and biotech companies in the design of development plans capable of accelerating the successful transition to the proof-of-concept stage (phase II).

According to present standards, phase I protocols are the most complex and demanding to execute. There is a wide variability in protocol complexity across the therapeutic segments, within and between early clinical research phases, so that the sponsor can obtain critical clinical information, get their money’s worth, and subsequently make crucial decisions early
in the development process.