Patient compliance clinical trials

In many clinical trials a positive control of a clinically established drug is often used for comparison purposes for example, a novel selective serotonin reuptake inhibitor (SSRI), may be compared with a more established tricyclic antidepressant, such as imipramine. The aim is to see whether the new SSRI is more efficacious or has fewer adverse side effects than the more established tricyclic (Chapter 12). In many such comparisons the new and older treatments are equally efficacious at relieving depression, but the newer drugs display fewer side effects this means that they are better tolerated by patients, so that they are more willing to continue taking the tablets. The high rates of compliance also mean that, in overall terms, newer drugs with fewer side effects tend to be more efficacious. 

Regulatory authorities play an important and active role to ensure regulatory compliance in the conduct of a clinical trial. Agencies such as the FDA inspect clinical studies. An inspection of a trial may reveal that the protocol is not being followed strictly, the Investigator may not be involved with the project as much as is expected, there may be a lack of patient care, changes to the protocol may not have been relayed to the IRB, and so on. In such cases, corrective actions have to be implemented immediately and the FDA must be satished before the trial can continue. Deficiencies found are reported on Form 583. 

A 5 year randomized clinical trial in the United States found that in spite of the availability of hypertensive medication, awareness promotions, and guidelines, only a third of all the hypertensive patients have their blood pressure under effective control due to noncompUance in medication. More tailored behavioral management intervention may help to improve compliance and achieve better control. 

All formulations for administration to humans must be prepared in compliance with good manufacturing practice (GMP) and the certificates of analysis must be provided. The European Clinical Trials Directive requires that details of the formulations be provided to, and approved by, regulatory authorities and a qualified person at the investigator site(s). In principle, the Directive has been in force throughout the EU since May 2004 though it has been implemented at various times in different member states. The Directive applies to healthy volimteer as weU as patient studies. The requirements for pharmaceutical products for administration to humans are summarised in Box 4.6. 

The IRB is responsible for judging all studies to be conducted at the centre concerned by reviewing protocols, the informed consent sheet, the investigator s brochure and other materials relating to the conduct of clinical trials. The IRB is also responsible for monitoring whether the clinical trials are conducted in compliance with both GCP and IRB s requirements, if any. When the study period of a clinical trial exceeds 1 year the IRB should review the study every year. As the new GCP allows the study sponsor to pay a reasonable amount of money to the study subjects, the IRB is expected to review whether the amount and method of payment is reasonable and does not infringe upon the ethical aspects of the study. Also, the advertisement of a trial for patient recruitment is allowed, but the IRB s approval to implement this at the study centre is required. 

The recommended dose is two 333 mg tablets (total dose, 666 mg) taken 3 times daily. Although dosing may be done without regard to meals, dosing with meals was employed during clinical trials and is suggested as an aid to compliance in those patients who regularly eat 3 meals daily. A lower dose may be effective in some patients. 

Among patients with bipolar disorder, schizophrenia and major depression the prevalence of comorbid substance use disorders may be as high as 50%. Substance use disorders are usually associated with Axis [I (personality) disorders, poor treatment compliance and poorer response to pharmacotherapy exclusion or at least adequate diagnosis of these patients is therefore essential for clinical trials. 

The reported incidence of resistance to these drugs varies greatly, from less than 5% to 75%. In part this tremendous variation in incidence reflects the definition of resistance (recurrent thrombosis while on antiplatelet therapy vs in vitro testing), methods by which drug response is measured, and patient compliance. Several methods for testing aspirin and clopidogrel resistance in vitro are now FDA-approved however, their utility outside of clinical trials remains controversial. 

Examples of product quality GxP data include study data (e.g., stability trial data, clinical trial data, patient and animal records/results), regulatory submissions (e.g., stability data, development summary reports), analytical production data (e.g., analytical methods, quality reference data), and compliance management (e.g., indexes to archived documents/records). 

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