Patient recruitment

The Changing Role of Clinical Research Associates Patient Recruitment Reduced Time to Database Lock Management of Geographically Diverse Studies... 

SPILKER B, CRAMER J A (1992) Patient recruitment in clinical trials. New York, Raven Press. 

In the past 20 years, the average number of trials per new drug has increased from 30 to more than 70. The number of patients recruited for testing a drug in a typical submission for marketing approval has increased from about 1500 to 5200. 

The first consideration, as always, will be safety information that can be obtained more safely in healthy subjects, which may subsequently reduce risk to patients, should prompt a debate on whether it is wise to progress according to plan or whether an additional study should be performed in healthy subjects. Another option that may be considered is to proceed with the planned study in patients but to admit them to hospital or a clinical investigation unit for all or part of the dosing period. However, this might not be feasible because suitable facilities and staff are not available or because the anticipated rate of patient recruitment might be considered unacceptably slow. 

There are of course practical considerations in clinical research. We may find patient recruitment difficult in single centre studies and this is one of the major drivers to multicentre and multinational trials. Alternatively, we may need to relax the inclusion/exclusion criteria or lengthen the recruitment period. Unfortunately, while each of these may indeed increase the supply of patients they may also lead to increased variability that in turn will require more patients. A second issue is the size of the CRD which, if it is too small, will require a large number of patients. In such circumstances we may need to consider the use of surrogate endpoints (Section S.3.3.2). Finally, the standard deviation may be large and this can have a considerable impact on the sample size - for example, a doubling of the standard deviation leads to a four times increase in the... 

Surrogate endpoints should be carefully chosen, if they are required. Some surrogate endpoints, such as peak flow in asthma or haemoglobin Ale in diabetes mellitus, are well established and can be used in the confirmation studies. Conducting true endpoint study is difficult if it is not incorporated into global study because patient recruitment is still slow in Japan and hence relatively small number of study participants will be achieved in a reasonable time frame. 

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. 

Patient recruitment advertisement often appears in major newspapers or leaflets, which are delivered with newspapers, as most households prescribe one or more major newspapers. Some CROs established call centres to handle patient/volunteer applications or queries regarding the clinical trial and introduction of participating hospitals. 

One concern with equivalence and non-inferiority trials is that a positive conclusion of equivalence/non-inferiority could result from an insensitive trial by default. If, for example, equivalence is established then this could mean either that the two treatments are equally effective, or indeed equally ineffective. If chosen endpoints are insensitive, dosages of the drugs too low, patients recruited who are not really ill and the trial conducted in a sloppy fashion with lots of protocol deviators and dropouts, then the treatments will inevitably look very similar Clearly we must ensure that a conclusion of equivalence/non-inferiority from a trial is a reflection of the true properties of the treatments. The regulatory guidelines (ICH ElO) talk in terms of assay sensitivity as a requirement of a clinical trial that ensures this. 

The Berkeley Program. The first heavy-ion therapy program was initiated at Berkeley, and 433 patients were treated between 1975 and 1992 [47]. The program was limited by the availability of the machine and its complexity (which resulted in many unscheduled down times), and, as a consequence, there was a patient recruitment problem. 

Unfortunately, several neutron therapy centers were closed for technical reasons or patient recruitment difficulties. However, the centers applying neutron therapy today benefit from the same conditions of safety, reliability, and physical selectivity as photon therapy centers. 

Another important factor that may favor placebo responses in clinical studies is probably the patient recruitment strategy, as suggested by the following observation two almost identically designed studies with fluoxetine vs. placebo in the treatment of post-traumatic stress disorder (PTSD) were performed, but only one of them resulted in a significant difference between... 

Patients recruited by advertisement may cause higher placebo response rates than the spontaneously incoming patients of out-or inpatient departments... 

Minimize participation of patients recruited by means of advertisement... 

For food allergens, validated animal models for dose-response assessment are not available and human studies (double-blind placebo-controlled food challenges [DBPCFCs]) are the standard way to establish thresholds. It is practically impossible to establish the real population thresholds this way. Such population threshold can be estimated, but this is associated with major statistical and other uncertainties of low dose-extrapolation and patient recruitment and selection. As a matter of fact, uncertainties are of such order of magnitude that a reliable estimate of population thresholds is currently not possible. The result of the dose-response assessment can also be described as a threshold distribution rather than a single population threshold. Such distribution can effectively be used in probabilistic modeling as a tool in quantitative risk assessment (see Section 15.2.5)... 

The availability of scanning equipment and trained personal, specific contraindications, patient claustrophobia, and the safety of the sometimes very ill or uncooperative stroke patients limit the feasibility of stroke MRI during the scan. To determine the true feasibility of MRI requires a prospective study in all patients presenting with suspected stroke. Singer et al. (2004) found that only 80% of 144 stroke patients recruited at the hospital door could be examined with MRI. Others reported even smaller numbers between 54% and 62% of the patients in whom MRI was feasible (Barber et al. 2005 Hand et al. 2005 Schramm et al. 2004). According to Barber et al. (2005) and Hand et al. (2005), feasi-... 

Care is needed in deciding what practical action should be taken on the basis of this result. Remember that a non-significant result does not preclude a difference. Leaflet B has quite a strong lead over its competitors and our experiment may simply have inadequate power to detect a genuine superiority. This is another demonstration of how frustrating this type of data can be —90 patients recruited and interviewed and we still are not sure if it matters which leaflet we use ... 

Typically these studies cost from 1.5 to 3 million to conduct. Based on the perceived probability of a significant QT interval effect (based on preclini-cal studies, class effects, and ECG data from phase 1 studies) a decision must be made whether to conduct the definitive QT study prior to proceeding with a proof-of-concept study in patients, or whether to delay this study until the proof of concept (POC) has been demonstrated. Of note, for many biophar-maceutical products it would not be possible nor ethical to dose to steady state in healthy volunteers, to dose at two to four times anticipated therapeutic exposures, or to use a crossover design with reasonable washout periods. Thus a QT study performed with a biopharmaceutical may need to vary from the usual design and the E14 guidance, and may present great challenges for subject or patient recruitment. 

Availability of subject population Assess the plan for patient recruitment. Ascertain the anticipated rate of enrollment and the accessibility to an adequate number of suitable subjects to conduct the study. Note subjects in waiting area of investigational site/office. The need for advertisement is reviewed. 

It is now widely believed that the greatest impact on reducing development cycle time will come from more effective conduct of clinical trials—in essence, at the point at which patients are recruited and clinical data are collected. The study conduct arena offers many opportunities for incremental improvement, from site selection through IRB approval, patient recruitment and enrollment, and data collection. 

The SMOs in this group own and operate the sites in their network. These providers primarily vary by whether each site in its network has a staff physician serving as the principal investigator, or whether the center primarily contracts with area physicians to fill the role of the principal investigators. Corporate-owned SMO providers that do not have staff medical directors will typically staff each of their centers with a site manager, study coordinators), and, lately, patient recruitment specialists. Physicians are paid on a fee-for-service or hourly basis. Depending on the trial, patients are seen either at the physician s office or at the SMO s own facilities. 

The strength of this model is that investigators are practicing physicians. In terms of patient recruitment, this type of SMO has access to a greater number of patients through its members patient databases. The SMO may supplement this core resource with advertising and its own corporate database, but the majority of the patients are likely to come from the physicians own patient community. 

Sponsors and CROs are looking for study conduct providers that offer fewer-stop shopping, combined with highly effective patient recruitment and retention, and ease of entry and market penetration. As a result, the following are becoming increasingly important site selection criteria ... 

These and other factors identified as being associated with early stroke risk (Gladstone et al. 2004 Hill et al. 2004) were used to derive the ABCD score, a predictive tool of stroke risk within seven days after TIA (Rothwell et al. 2005). Briefly, all clinical features that had previously been found to be independently predictive of stroke after TIA were tested in a derivation cohort of 209 patients recruited from the Oxfordshire Community Stroke Project (OCSP, Lovett et al. 2003). Any variable that was a univariate predictor of the seven-day risk of stroke with a significance ofp < 0.1 assessed with the log rank test was incorporated into the score. The score was then validated in three further independent cohorts. 

Although there is a consensus that encainide and flecainide were associated with an increase in the rate of mortality in CAST, there are stiU some open questions. First, all the patients recruited to CAST had asymptomatic ventricular dysrhjdhmias after myocardial infarction, and it is not clear whether the results can be extrapolated to other patients. Secondly, the reasons for the increased mortality in the treated patients are not clear ventricular dysrhythmias and worsening of left ventricular function are both possible. Thirdly, it is not clear whether the results of CAST in patients with asymptomatic ventricular dysrhythmias after myocardial infarction can also be applied to other Class I antidysrhythmic drugs. 

A third variety, so-called delayed-onset heparin-induced thrombocytopenia has also been described in several reports. In 12 patients, recruited from secondary and tertiary care hospitals, thrombocytopenia and associated thrombosis occurred at a mean of 9.2 (range 5-19) days after the withdrawal of heparin nine received additional heparin, with further falls in platelet counts (32). In a retrospective case series, 14 patients, seen over a 3-year period, developed thromboembolic complications a median of 14 days after treatment with heparin (33). The emboli were venous (n — 10), or arterial (n — 2), or both (n — 2) of the 12 patients with venous embolism, 7 had pulmonary embolism. Platelet counts were mildly reduced in all but two patients at the time of the second presentation. On readmission, 11 patients received therapeutic heparin, which worsened their clinical condition and further reduced the platelet count. 

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