Clinical programme

Box 3.1 Phases of the clinical programme Phase 1 Initial studies in man to determine tolerance and the safe dosage range and to give an indication to metabohc handling. These studies are usually undertaken with healthy volunteers but may be extended to include patients. Humans exposed 30-50... 

Having established the number of patients to be included in the preregistration clinical programme, it is important to consider how these will be distributed and hence how many studies are required. This is very variable. The Tufts Institute reported that, for biopharmaceuticals. 

The case report form (CRF) should be unambiguous and simple to use. Its completion should minimise the need for text. CRFs should consist of three modules. One module is common for all trials (laboratory data, etc.), one is common for all trials in the clinical programme for a given compound and one is specific to the study in question. In this way, data handlers become familiar with the forms and can therefore manage a larger number with fewer mistakes. A mechanism should be in existence to ensure that the clinician completes the CRF adequately. 

One of the measures of the quality of the preregistration clinical programme is the total time from the decision to enter full development to the first regulatory approval in a major market. It is also important to monitor quality in other ways. One option is to assess the frequency with which predetermined milestones are achieved. More subtly, quality can be assessed by examining the number of incomplete, inaccurate or indecipherable CRFs that are returned or the number of protocol amendments made which are not based on new information. Milestones may still be achieved when quality is poor, that is, when there is inefficiency, but this means that they were wrongly established and can be improved if efficiency improves. 

Data not usually available until after the end of the Phase III clinical programme... 

In this section we consider the requirements for the clinical programme leading to global registration, as well as other studies which will form part of the overall programme. Scheduling is covered elsewhere in this volume. 

Overall, the clinical programme has been designed to assess safety and efficacy in a wide range of patient populations, from newborn to pediatric and adult patients, and chnical settings. 

For many biopharmaceuticals, pharmacodynamics outlasts pharmacokinetics and this may result in delayed toxic effects and may also affect the potency as well as the toxicity of subsequent doses (this is the so-called first-dose effecf), and may impact other biochemical/physiological pathways. Therefore, the clinical programme must be capable not only of demonstrating efficacy, but also detailed safety by also detecting long-term and unexpected toxicities. 

On 8 September 2008 the European Medicines Agency announced that Takeda, the manufacturers of ramelteon, had withdrawn its application for marketing authorization for ramelteon for the treatment of primary insomnia in patients over the age of 18 years with a view to extending its clinical programme to address outstanding questions on the benefit to harm balance this followed a negative recommendation from the regulators in June 2008 [131. ... 

These considerations led to a clinical programme of research comparing omeprazole with placebo, ranitidine and misoprostol for prophylaxis, healing and maintenance of NSAID-associated ulcers and multiple erosions. 

On the basis of long-lasting clinical programmes, the most important synthetic nondegradable polymers in bone tissue engineering are polyethylene (PE),... 

The choice of toxicity studies, and the design of individual studies, will depend on the proposed clinical programme. Important issues to consider are ... 

An example of how this approach might be used to support a clinical programme is shown in Table 10.2. This approach can also support human clinical evaluation of a new gene in the same vector, or a new vector, without the need to repeat the entire preclini-cal programme. 

---