Fast Facts: Clinical Trials in Oncology

The fundamentals of design, conduct and interpretation

A. Hackshaw, G.C.E. Stuart

• Publisher: S. Karger
• Year: 2020
• ISBN:
  9781912776740
• Topic: Medizin
• Subtopic: Onkologie

Written by leading experts, 'Fast Facts: Clinical Trials in Oncology' will enhance the reader's ability to critically evaluate published evidence. Assuming little or no prior knowledge, the book sets out clearly the fundamental features of clinical trials. The key attributes of Phase I–III trials of pharmaceutical products are described, as are trials of surgical procedures, radiation therapy and advanced therapies. The processes and documentation required to set up and conduct a trial are outlined, and the authors describe how trial data and real-world evidence are used to improve care. Although this concise colorful book focuses on oncology, the principles apply equally to interventions in other areas of practice. It will prove invaluable to medical, pharmaceutical and allied health professionals who want, or need, an overview of how contemporary clinical trials are designed and conducted.

1	Fundamental features of clinical trials

This chapter outlines the main features of cancer trials, providing a framework for subsequent chapters. Few new drugs transit the full trajectory from laboratory discovery to clinical practice. Between 2003 and 2011, only 7% of oncology drugs investigated in Phase I–III trials received regulatory approval from the US Food and Drug Administration (FDA).¹ Modern trials present various challenges for the pharmaceutical industry^2,3 and academic and public sector organizations, including administrative burden and high costs. Nevertheless, trials continue to play a central role in research on prevention and treatment.

What is a clinical trial?

A clinical trial is an experimental research study in which some or all of the participants receive an intervention that they would not normally have.

The development of most interventions typically takes 5–15 years from inception through to being recommended for routine care. During this time, several clinical trials provide the main evidence relating to benefit and harms (Figure 1.1). Drugs and some medical devices require a marketing authorization (license) followed by a process of market access that allows them to be provided to the particular patient population (see Chapter 7 and Table 7.1).

Figure 1.1 The drug development process. Phases may be combined (for example, Phase I/II or II/III). Market authorization (license) and market access are outlined in Chapter 7. HTA, health technology assessment.

Clinical trials are classified into Phases I–IV, with different objectives and designs (Table 1.1). Table 1.2 outlines the main design features of clinical trials, described further in the following sections. These features form the trial protocol (the most important document), along with the justification for the study, biological plausibility for the proposed interventions, specific objectives, statements about Phase (I–IV), recruitment processes, safety monitoring and an outline of the main statistical analyses.

TABLE 1.1 Key features of oncology trials
Phase	Typical number of patients	Design	Primary aims
I	<50	Usually at least one patient cohort and open label Can be first in human	•To show adequate safety •To find a dose (drug or radiation therapy) with tolerable toxicity •To examine biological and pharmacological effects
II	30–100 per group	May be single arm or have several arms, including a comparator (control)	•To obtain a preliminary estimate of efficacy •To further evaluate toxicity •May inform design of Phase III trial
III	Several hundred or thousand patients	Must be randomized and include a comparator group	•To provide definitive evidence on whether a new treatment is better than the control (superiority), similarly effective (equivalence) or not materially worse but with other advantages (non-inferiority)
IV*	Several hundred or thousand patients	Patients from real-world practice Not usually randomized	•To monitor efficacy and safety in the population once the new treatment is used in routine practice •May identify uncommon adverse events not seen in Phase II or III trials
*Also referred to as postmarketing surveillance/pharmacovigilance studies.

TABLE 1.2 Key design features of clinical trials
Feature	Explanation
Eligible patient population	Which patients can be recruited (inclusion and exclusion criteria)
Interventions	Details of the new and comparator treatments, and whether randomization and blinding (placebo) are used
Outcome measures (endpoints)	Primary: one endpoint (sometimes two or three) considered to be the most clinically relevant Secondary: supportive evidence Translational research: biomarkers in blood, tissue or urine samples, or imaging scans
Follow-up	Type, number and timing of clinic visits and assessments, and biological specimen collection required to measure outcomes and monitor patient safety
Sample size	Justification for the number of patients required, usually to demonstrate a statistically significant difference in the primary endpoint

Objectives

Each trial will have several objectives (aims or hypotheses). Each objective is typically associated with a clearly defined quantitative outcome measure. The primary objective is meant to inform what happens after the trial if the objective is met, such as a change in practice or further studies. A simple primary objective is to determine whether drug X improves overall survival (OS) in patients with cancer Y compared with standard drug Z. Another example is whether drug A given before surgery (as neoadjuvant therapy) leads to successful complete resection of the tumor.

Secondary objectives (with corresponding outcome measures) provide supporting evidence, although they often also influence decision-making. Examples of secondary objectives include safety and adherence to treatment, and they can be used to provide further knowledge about an intervention (such as whether certain patients benefit more than others) or to find prognostic and predictive markers.

Phase III and many Phase II trials have one of the following general efficacy objectives:

•superiority: the new treatment is more effective than the comparator (or what is expected using current standards of care)

•non-inferiority: the new treatment is not much worse than the comparator

•equivalence: the efficacy of the new treatment is similar to that of the comparator.

Most are superiority or non-inferiority trials. For non-inferiority and equivalence, the new treatment is expected to be safer, cheaper, easier to administer or have a better health-related quality of life (HRQoL) profile than the comparator (see Figure 4.1).

Patients

Patients are usually enrolled at the point of care, where staff will identify and approach potentially eligible patients. The trial protocol will specify the inclusion criteria (which patients can participate in the trial) and exclusion criteria (which patients should not take part). These criteria aim to ensure that only patients likely to benefit from the new t...