Clinical trials patient recruitment

It is often difficult for patients to learn about opportunities to participate in clinical trials. Doctors and patient advocacy groups can be valuable resources for patients in search of clinical trial information. Newspapers, particularly in large cities, often carry clinical trial recruitment advertisements. A call to the relevant department at nearby university medical centers can lead to information about clinical trials currently recruiting patients. 

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

The most common criticism of our meta-analysis is the claim that the clinical trials we analysed were flawed, and that better results would have been found if the studies had been designed better. The trials were too short to show the real effect of antidepressants, the critics said. The people recruited to participate in them were not depressed enough, or they were too depressed. In any case, they were not representative of the patients who are generally seen in clinical practice. 

Most clinical trials, including the ones my colleagues and I analysed, are conducted on volunteers, many of whom are recruited for the trial by advertisements. Perhaps these depressed people are not as responsive to antidepressants as the patients seen in clinical practice. The STAR D trial that I described earlier was designed specifically to evaluate the effect of antidepressants on the kinds of patients who are typically seen in clinical practice. None of the patients in this trial were recruited by advertising. Instead, they were all patients who sought treatment for depression in family practice or psychiatric out-patient treatment facilities. Also, the usual exclusion criteria were relaxed, so that a broader range of patients was evaluated. The trial did exclude patients who had already tried antidepressants but had not responded to them, although this exclusion should result in better response rates, not worse ones. 

China offers a large pool of treatment naive patients for clinical trials. There are 1.3 bUhon people, of which 250 milhon are insured and another 250 million partially insured. Chnical trials are one-third the cost of that in the United States and recruitments are expected to be rapid. However, comphcating factors are slower regulatory processes, limited qualified central laboratories for testing, and restriction of export of blood and serum samples outside China for testing. 

Citicoline (cytidinediphosphate-choline/CDP-choline 26) is an intermediate in the biosynthesis of acetylcholine. It has been extensively used for the treatment of neurodegenerative disorders associated with head trauma, stroke, brain aging, and AD. Studies in mice have indicated a protective effect of citicohne against memory impairment induced by adverse environments. A human study recruited 30 patients with mild to moderate AD in a double-blind, randomized and placebo-controlled clinical trial... 

The limitations of the use of biomarkers in healthy volunteers must be recognised. For example, although there have been attempts to simulate migraine headache in volunteers, to date none of these models can be considered adequate to serve as a surrogate endpoint. Patients with migraine are not difficult to recruit and are usually healthy apart from their migraine. In this case, it maybe more appropriate to establish tolerability and pharmacokinetics in healthy volunteers and then to select a maximum well-tolerated dose with which to perform a small proof of principle clinical trial in patients. This will need to be followed by larger trials to establish the dose-response relationship. 

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... 

As anyone involved in the conduct of clinical trial knows, it is notoriously difficult to estimate the length of time it will take to recruit patients into a study. Formal inclusion and exclusion criteria can severely restrict the number of patients suitable for a trial, even when common conditions are being studied. An additional and common complication is the overoptimistic investigator syndrome. ... 

Currently, the agency recommends sponsors to recruit more than 10 patients at each centre, and most of the study centres are able to accommodate this number. As the overall number of clinical trials has declined because of the new GCP guidelines and unfavourable pricing rules for the new products, with limited advantage over existing products, it has become relatively easy for the sponsors to meet such requirements than before. 

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. 

Pharmaceutical Affairs Law prohibits advertisement of non-approved drugs, that is, clinical study drugs. But if the study drug is not identified, the sponsor can advertise the clinical trial itself in order to recruit patients. 

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. 

It is important to recognize, however, that the U.S. Code of Federal Regulations does not address the question of gender in clinical trials there is no formal requirement that women make up a significant portion of a trial s patient population or even participate at all. The reality is that unless a trial specifically mandates female participation (e.g., a test for the safety and efficacy of a new birth control pill), men overwhelmingly predominate as subjects in clinical trials. For pharmaceutical companies, there is little motivation to recruit women. The first reason for this lack of motivation has to do with attempts to limit potential liabilities. Other concerns stem from this issue and focus on economic and legal realities that are stumbling blocks to expanded inclusion of women in research. 

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