Download (direct link):
Phase III clinical trials are designed to assess the safety and efficacy characteristics of a drug in greater detail. Depending upon the trial size, hundreds if not thousands of patients are recruited, and the trial may last for up to 3 years. These trials serve to assess the potential role of the new drug in routine clinical practice — the phase III results will largely dictate whether or not the prospective drug subsequently gains approval for general medical use.
Even if a product gains marketing approval (on average 10-20% of prospective drugs that enter clinical trials are eventually commercialized), the regulatory authorities may demand further post-marketing surveillance studies. These are often termed ‘phase IV clinical trials’. They aim to assess the long-term safety of a drug, particularly if the drug is administered to patients for periods of time longer than the phase III clinical trials. The discovery of more longterm unexpected side effects can result in subsequent withdrawal of the product from the market.
Both pre-clinical and clinical trials are underpinned by a necessity to produce sufficient quantities of the prospective drug for its evaluation. Depending on the biopharmaceutical product, this could require from several hundred grams to over a kilo of active ingredient. Typical production protocols for biopharmaceutical products are outlined in detail in Chapter 3. It is important that a suitable production process be designed prior to commencement of pre-clinical trials, that the process be amenable to scale-up and, as far as is practicable, that it is optimized (Figure 2.9). The material used for pre-clinical and clinical trials should be produced using the same process by which it is intended to undertake final commercial-scale manufacture.
Figure 2.9. Scale-up of proposed biopharmaceutical production process to generate clinical trial material, and eventually commercial product. No substantive changes should be introduced to the production protocol during scale-up
THE DRUG DEVELOPMENT PROCESS 75
Extensive early development work is thus essential. Any significant deviation from the production protocol, used to generate the trial material, could invalidate all the clinical trial results with respect to the proposed commercialized product (changes in the production process could potentially change the final product characteristics — both the active ingredient and contaminant profile).
Clinical trial design
Proper and comprehensive planning of a clinical trial is essential to the successful development of any drug. Clinical trial design is a subject whose scope is too broad to be undertaken in this text, and only a brief overview of the subject is presented below. The interested reader is referred to the Further Reading section at the end of this chapter. The general principles presented below are relevant to phase II, and particularly phase III, clinical trials. As the bulk of the estimated $300-500 million required to develop a drug is spent on clinical trials, a poorly planned and/or executed clinical trial can be very costly to the drug developer.
The first issue to be considered when developing a trial protocol is to define precisely what questions the trial results should be capable of answering. As previously discussed, the terms ‘safety’ and ‘efficacy’ are difficult to define in a therapeutic context. An acceptable meaning of these concepts, however, should be committed to paper prior to planning of the trial.
Trial size and study population
A clinical trial must obviously have a control group against which the test (intervention) group can be compared. The control group may receive (a) no intervention at all; (b) a placebo (i.e. a substance such as saline, which will have no pharmacological or other effect); (c) the therapy most commonly used at that time to combat the target disease/condition.
The size of the trial will be limited by a number of factors, including:
• economic considerations (level of supporting financial resources);
• size of population with target condition;
• size of population with target condition after additional trial criteria have been imposed (e.g. specific age bracket, lack of complicating medical conditions, etc.);
• size of eligible population willing to participate in the trial.
While a comprehensive phase III trial would require at least several hundred patients, smaller trials would suffice if, for example:
• the target disease is very serious/fatal;
• there are no existing acceptable alternative treatments;
• the target disease population is quite small;
• the new drug is clearly effective and exhibits little toxicity.
Choosing the study population is obviously critical to adequate trial design. The specific criteria of patient eligibility should be clearly pre-defined as part of the primary question the trial strives to answer.
A number of trial design types may be used (Table 2.6), each having its own unique advantages and disadvantages. The most scientifically pure is a randomized, double-blind trial (see later). However, in many instances, alternative trial designs are chosen based on ethical or other grounds. In most cases, two groups are considered: control and test. However, these designs can be adapted to facilitate more complex sub-grouping.