Discontinuation studies design

Discontinuation trials, either controlled or open, usually are not likely to have any direct benefit and may well have real risks, such as relapse, suicide, and loss of employment. Such studies need additional scrutiny and safeguards to minimize risk and to strengthen consent procedures. There are some situations in which a discontinuation study may be considered. For example, to determine whether long-term treatment is needed, a study design might randomly assign patients who have responded successfully to a particular treatment to either a continuation or discontinuation of that treatment. Relapse rates across these two conditions could... 

Figure 18.1 Study design for the pre- and postnatal development evaluation in the cynomolgus monkey. Maternal treatment is either discontinued at term or is continued into the lactation period in order to investigate transfer of test item to the infant. Transfer of biopharmaceuticals via milk has been observed in this species. The duration of the postnatal observation period is variable and not yet standardized. In our laboratory the longest postnatal observation period covered 720 days. A variety of parameters is available for testing infant development (see also Table 18.4 for details). For biopharmaceuticals, a minimum period of 6 months appears appropriate. If the behavioral test battery comprises learning tests that are recommended from the age of 6 months onward, infants should be observed for at least 9 months.

This second group of tests is designed to measure the mechanical response of a substance to applied vibrational loads or strains. Both temperature and frequency can be varied, and thus contribute to the information that these tests can provide. There are a number of such tests, of which the major ones are probably the torsion pendulum and dynamic mechanical thermal analysis (DMTA). The underlying principles of these dynamic tests have been covered earlier. Such tests are used as relatively rapid methods of characterisation and evaluation of viscoelastic polymers, including the measurement of T, the study of the curing characteristics of thermosets, and the study of polymer blends and their compatibility. They can be used in essentially non-destructive modes and, unlike the majority of measurements made in non-dynamic tests, they yield data on continuous properties of polymeric materials, rather than discontinuous ones, as are any of the types of strength which are measured routinely. 

T-1249 demonstrated substantial activity against enfuvirtide-resistant viruses in clinical studies (Melby et al. 2007a) however, development was discontinued due to formulation issues. Additional peptides with more potent activity were subsequently designed, which also showed much improved pharmacokinetic properties (Dwyer et al. 2007) however, the availability of oral agents in other new classes makes the likelihood of the development of these agents uncertain. 

In general, the SSRIs have a more tolerable side effect profile than the tricyclic antidepressants with their anticholinergic effects. Review of the rate that subjects in the controlled studies discontinued a SSRI because of adverse effects provides some perspective on how well tolerated the medications are, although the specifics may vary according to dosage and design (e.g., forced titration) and are not directly comparable. The rate of discontinuation was reported to be 12% (4/48) for fluoxetine (Emslie et ah, 1997), 9.7% for paroxetine (Keller et ah, 2001), 13% (12/92) for sertraline (March et ah, 1998), and 33% (19/57) (Riddle et ah, 2001) and 7.9% (5/63) for fluvoxamine (Walkup et ah, 2001). 

---