The objectives of each phase, in a somewhat idealised pathway, of a typical development programme for a new drug are summarised in Figure 7.1 and range from studies to determine the pharmacokinetic profile of a drug in healthy volunteers to large-scale randomised comparative trials. However, some of these steps may be taken in parallel and even simultaneously in the same subjects.
The nomenclature of Phase I, II and III has been developed for drug development but they essentially apply (although modifications may be necessary) to new approaches to surgery, radiotherapy, medical devices and combinations of such procedures. They also extend beyond merely therapeutic trials to planning, for example, trials comparing alternative forms of contraception in women, and trials evaluating alternative health promotion interventions. However, in some instances, such as in trials comparing educational packages, they may start at the Phase III stage without involving the earlier phases.
Although there is not always a clear division between preclinical studies and clinical trials, the essential difference is that in the latter there is usually some therapeutic intent. As a consequence, even in a very early dose-escalation Phase I trial in a patient with a malignancy, there is a concern not to give too little of a drug as such a dose would be extremely unlikely to bring any (anti-tumour) benefit to the patient. Thus an early stage clinical trial may include in the design some assessment of response as for a Phase II trial.
If these trials are concerned with patients, as opposed to 'healthy' controls, then careful note of this fact must play a role in determining those who are eligible for the trial. These considerations will differ from phase to phase in the drug development process, the particular treatment modality under consideration, the severity of the disease and many other factors.
At some stage in the drug development process a new compound moves from the laboratory and is then usually tested in animals prior to its introduction in humans. A first step into humans may be to determine the pharmacokinetic properties of the drug in healthy volunteers. Studies carried out primarily to address pharmacokinetic issues are often referred to as ADME studies, since they are designed to characterise four fundamental aspects of a drug's kinetics: Absorption, Distribution, Metabolism, and Excretion. In some circumstances the profile may need to be determined in patients, rather than in healthy volunteers, as the disease itself may affect the pharmacokinetic properties in an important way. These studies may be comparative in nature when assessing the bioequivalence of a new compound as compared to a previous standard.
Example - PK profile of sumatriptan tablets - migraine relief
Walls, Lewis, Bullman et al. (2004) describe the PK profile of a new form of sumatriptan tablets for potential use for patients with migraine. In their study healthy subjects were used. They concluded that the new form was bioequivalent to sumatriptan conventional tablets and was absorbed more quickly.
After the ADME studies, or in parallel, a Phase I clinical trial commences in patients. Typically a Phase I trial takes the form of testing a range of doses suggested by studies in the laboratory animal or by comparison with those drugs with similar properties. The trial aims to determine which of these chosen doses (if any) should be passed to the next phase of development to determine its activity. The dose is often chosen on the basis of the highest feasible with an acceptable toxicity profile. The definition of 'acceptable toxicity' and how it is to be assessed is crucial to this phase.
Example - Phase I trial - unresectable pancreatic cancer
Muler, McGinn, Normolle et al. (2004) describe a Phase I trial in which 19 patients with pancreatic cancer were treated with cisplatin combined with gemcitabine and radiation therapy (RT). They concluded that cisplatin doses up to 40 mg/m2 could be safely added to full-dose gemcitabine and conformal RT.
Once the dose of a compound is recommended from a Phase I study, then activity at that dose may be tested in a Phase II trial. Such studies, although not generally comparative in nature, will often be designed with the knowledge that other compounds are active for the disease in question, so that evidence of at least this minimum activity may be sought. The definitions of how 'activity' is defined and assessed are crucial to this phase. If sufficient activity is demonstrated then this may suggest testing for efficacy in a randomised Phase III comparative trial.
Example - Phase II trial - carcinosarcoma of the female genital tract
Van Rijswijk, Vermorken, Reed et al. (2003) conducted a Phase II trial in 48 women with carcinosarcoma of the genital tract. Although the activity of the combination of cisplatin, doxorubicin and ifosfamide was established (overall response rate 56%), they did not recommend this treatment combination but suggested that those 'with more favourable toxicity profiles should be explored'.
It is clear from this example that Phase II trials are not confined to those testing a single agent.
PHASE III TRIALS
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