Discontinued Studies

Under this heading we will consider shortly two situations, which may sometimes occur in a test facility or at a sponsor, and which may be judged as problematic with regard to their GLP compliant handling. 

Obviously no final report would be written, and no Quality Assurance statement could be issued, and the unfinished study would thus not be in compliance with GLP. 

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Adrenocorticotropic hormone (ACTH) gel, 40 to 80 USP units, may be given intramuscularly every 6 to 8 hours for 2 to 3 days and then discontinued. Studies with ACTH are limited, and it should be reserved for patients with contraindications to first-line therapies (e.g., heart failure, chronic renal failure, history of GI bleeding). 

There are no randomized, double-blind, controlled studies of hospitalized children and adolescents with acute mania. Two systematic, albeit open, studies of lithium in hospitalized, acutely manic adolescents had response rates of 67%-80% in classic manic adolescents, and 33%-40% in manic adolescents with prior ADHD (Strober et al., 1988 1998). In a discontinuation study in which manic adolescents stabilized on lithium were subsequently assigned double-blind to placebo or continuation treatment, the response rate was 53.5%, and the presence of prior ADHD made no difference in outcome (Kafantaris et al., 1998). However, the presence of psychosis decreased the likelihood of lithium response and antipsychotic medication was necessary for stabilization. Naturalistic discontinuation of lithium (because of noncompliance) after stabilization resulted in relapse rates of 90% vs. 37.5% for those remaining on lithium (Strober et al., 1990). A NIMH multisite study is currently examining this issue more systematically. 

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... 

Unlike the abrupt discontinuation study, severity and time course of withdrawal symptoms were similar for both short and long half-life agents. 

As pointed out by Hirai and Eyring (1959) the values of the compressibilities above and below Tg are so uncertain that we cannot even be sure that there is a discontinuity in the (non-equilibrium) values of (i at Tg. Weir (1953) was unable to find any discontinuity studying the compressibilities of vulcanized rubbers. However, Eq. (43) tells us that A fi cannot be zero because A a is not zero and Acv is not infinite. It is better to compute A ft from known values of A cv, T, V and A a. When this is done, the expected change in the internal pressure at Ta can then be calculated, see the next section. 

Methods of assessing rebound and withdrawal in more clinically relevant terms have been available for many years (e.g., [8]). In the past decade, regulatory authorities have insisted on discontinuation studies after short-term use as well as long-term maintenance or relapse prevention. This applies to hypnotics in equal force despite most product licences now restricting hypnotic use to short-term (2 1 weeks) use. An adequate number of subjects, normal and insomniac, must be studied. Rebound needs assessment over more than one night, with a variety of techniques including PSG, activity meters, and subjective reports. Standard sleep questionnaires can be used for the subjective assessments. 

Post-marketing surveillance and pharmacovigilance data contain few convincing cases of withdrawal from zopiclone. Most consist of rebound insomnia, but there are a few instances of withdrawal convulsions following high-dose dependence. A review of 25 zopiclone discontinuation studies found rebound effects and withdrawal symptoms to be minimal [35],... 

Liquid-phase chemistry is performed mostly in a discontinuous, batch-wise manner. It is then necessary, in order to get statistically significant results, to repeat the same experiment several hundred or even several thousand times with a cycle time on the order of a minute. Recent discontinuous studies... 

Trials that compare the relapse rate among people treated with lithium and people treated with placebo are thought to have established the efficacy of lithium for the prevention of recurrence in manic depression. However all these studies were actually discontinuation studies or involved discontinuing lithium in at least some subjects. Many earlier studies especially involved people who had taken lithium for many... 

Troost PW, Lahuis BE, Steenhuis MP, Ketelaars CE, Buitelaar JK, van Engeland H, Scahill L, Minderaa RB, Hoekstra PJ. Long-term effects of risperidone in children with autism spectrum disorders a placebo discontinuation study. J Am Acad Child Adolesc Psychiatry 2005 44 1137-44. 

Standard of care for diabetes and cardiovascular risk management should be provided. Retention and adherence are essential to the successful execution of the trial. Follow-up of all participants for the duration of the trial is critical, regardless of whether a participant discontinues study drug, because this is one of the most informative ways to demonstrate the integrity of the study and hence of the data generated. 

Hassler F, Glaser T, Pap AF, Beneke M, Diefenbacher A, Reis O. Zuclopenthixol Disruptive Behavior Study Group. A double-blind placebo-controlled discontinuation study of zuclopenthixol for the treatment of aggressive disruptive behaviours in adults with mental retardation-secondary parameter analyses. Pharmacopsychiatry 2008 41(6) 232-9. 

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